5- and 6-membered heterocyclic compounds

ABSTRACT

5- and 6-membered heterocyclic compounds which are inhibitors of phosphodiesterase 10 are described as are processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. Also described is the treatment of neurological, neurodegenerative and psychiatric disorders including but not limited to those comprising cognitive deficits or schizophrenic symptoms.

The disclosure relates to 5- and 6-membered heterocyclic compounds whichare inhibitors of phosphodiesterase 10. The disclosure further relatesto processes, pharmaceutical compositions, pharmaceutical preparationsand pharmaceutical use of the compounds in the treatment of mammals,including human(s) for central nervous system (CNS) disorders and otherdisorders which may affect CNS function. The disclosure also relates tomethods for treating neurological, neurodegenerative and psychiatricdisorders including but not limited to those comprising cognitivedeficits or schizophrenic symptoms.

BACKGROUND

Cyclic phosphodiesterases are intracellular enzymes which, through thehydrolysis of cyclic nucleotides cAMP and cGMP, regulate the levels ofthese mono phosphate nucleotides which serve as second messengers in thesignaling cascade of G-protein coupled receptors. In neurons, PDEs alsoplay a role in the regulation of downstream cGMP and cAMP dependentkinases which phosphorylate proteins involved in the regulation ofsynaptic transmission and homeostasis. To date, eleven different PDEfamilies have been identified which are encoded by 21 genes. The PDEscontain a variable N-terminal regulatory domain and a highly conservedC-terminal catalytic domain and differ in their substrate specificity,expression and localization in cellular and tissue compartments,including the CNS.

The discovery of a new PDE family, PDE10, was reported simultaneously bythree groups in 1999 (Soderling et al. “Isolation and characterizationof a dual-substrate phosphodiesterase gene family: PDE10A” Proc. Natl.Sci. 1999, 96, 7071-7076; Loughney et al. “Isolation andcharacterization of PDE10A, a novel human 3′,5′-cyclic nucleotidephosphodiesterase” Gene 1999, 234, 109-117; Fujishige et al. “Cloningand characterization of a novel human phosphodiesterase that hydrolyzesboth cAMP and cGMP(PDE10A)” J. Biol. Chem. 1999, 274, 18438-18445). Thehuman PDE10 sequence is highly homologous to both the rat and mousevariants with 95% amino acid identity overall, and 98% identityconserved in the catalytic region.

PDE10 is primarily expressed in the brain (caudate nucleus and putamen)and is highly localized in the medium spiny neurons of the striatum,which is one of the principal inputs to the basal ganglia. Thislocalization of PDE10 has led to speculation that it may influence thedopaminergic and glutamatergic pathways both which play roles in thepathology of various psychotic and neurodegenerative disorders.

PDE10 hydrolyzes both cAMP (K_(m)=0.05 uM) and cGMP (K_(m)=3 uM)(Soderling et al. “Isolation and Characterization of a dual-substratephosphodiesterase gene family: PDE10.” Proc. Natl. Sci. USA 1999,96(12), 7071-7076). In addition, PDE10 has a five-fold greater V_(max)for cGMP than for cAMP and these in vitro kinetic data have lead to thespeculation that PDE10 may act as a cAMP-inhibited cGMPphosphodiesterase in vivo (Soderling and Beavo “Regulation of cAMP andcGMP signaling: New phosphodiesterases and new functions,” Curr. Opin.Cell Biol., 2000, 12, 174-179).

PDE10 is also one of five phosphodiesterase members to contain a tandemGAF domain at their N-terminus. It is differentiated by the fact thatthe other GAF containing PDEs (PDE2, 5, 6, and 11) bind cGMP whilerecent data points to the tight binding of cAMP to the GAF domain ofPDE10 (Handa et al. “Crystal structure of the GAF-B domain from humanphosphodiesterase 10A complexed with its ligand, cAMP” J. Biol. Chem.2008, May 13^(th), ePub).

PDE10 inhibitors have been disclosed for the treatment of a variety ofneurological and psychiatric disorders including Parkinson's disease,schizophrenia, Huntington's disease, delusional disorders, drug-inducedpsychoses, obsessive compulsive and panic disorders (US PatentApplication 2003/0032579). Studies in rats (Kostowski et. al “Papaverinedrug induced stereotypy and catalepsy and biogenic amines in the brainof the rat” Pharmacol. Biochem. Behav. 1976, 5, 15-17) have showed thatpapaverine, a selective PDE10 inhibitor, reduces apomorphine inducedstereotypies and rat brain dopamine levels and increases haloperidolinduced catalepsy. This experiment lends support to the use of a PDE10inhibitor as an antipsychotic since similar trends are seen with known,marketed antipsychotics.

Antipsychotic medications are the mainstay of current treatment forschizophrenia. Conventional or classic antipsychotics, typified byhaloperidol, were introduced in the mid-1950s and have a proven trackrecord over the last half century in the treatment of schizophrenia.While these drugs are effective against the positive, psychotic symptomsof schizophrenia, they show little benefit in alleviating negativesymptoms or the cognitive impairment associated with the disease. Inaddition, drugs such as haloperidol have extreme side effects such asextrapyramidal symptoms (EPS) due to their specific dopamine D2 receptorinteraction. An even more severe condition characterized by significant,prolonged, abnormal motor movements known as tardive dyskinesia also mayemerge with prolonged classic antipsychotic treatment.

The 1990s saw the development of several new drugs for schizophrenia,referred to as atypical antipsychotics, typified by risperidone andolanzapine and most effectively, clozapine. These atypicalantipsychotics are generally characterized by effectiveness against boththe positive and negative symptoms associated with schizophrenia, buthave little effectiveness against cognitive deficiencies and persistingcognitive impairment remain a serious public health concern (Davis, J. Met al. “Dose response and dose equivalence of antipsychotics.” Journalof Clinical Psychopharmacology, 2004, 24 (2), 192-208; Friedman, J. H.et al “Treatment of psychosis in Parkinson's disease: Safetyconsiderations.” Drug Safety, 2003, 26 (9), 643-659). In addition, theatypical antipsychotic agents, while effective in treating the positiveand, to some degree, negative symptoms of schizophrenia, havesignificant side effects. For example, clozapine which is one of themost clinically effective antipsychotic drugs shows agranulocytosis inapproximately 1.5% of patients with fatalities due to this side effectbeing observed. Other atypical antipsychotic drugs have significant sideeffects including metabolic side effects (type 2 diabetes, significantweight gain, and dyslipidemia), sexual dysfunction, sedation, andpotential cardiovascular side effects that compromise their clinicallyeffectiveness. In the large, recently published NIH sponsored CATIEstudy, (Lieberman et al “The Clinical Antipsychotic Trials OfIntervention Effectiveness (CATIE) Schizophrenia Trial: clinicalcomparison of subgroups with and without the metabolic syndrome.”Schizophrenia Research, 2005, 80 (1), 9-43) 74% of patients discontinueduse of their antipsychotic medication within 18 months due to a numberof factors including poor tolerability or incomplete efficacy.Therefore, a substantial clinical need still exists for more effectiveand better tolerated antipsychotic mediations possibly through the useof PDE10 inhibitors.

BRIEF SUMMARY

Described herein are 5- and 6-membered heterocyclic compounds ofFormulas (I), (II) or (III) which are inhibitors of at least onephosphodiesterase 10 (e.g., PDE-10A):

Wherein:

HET is a heterocyclic ring selected from Formulas A1-A2, A6-A8, A10-A32and A38 below

and the left most radical is connected to the X group;W is selected from halogen, cyano, nitro, alkoxy, amino, alkylamino,dialkylamino, carboxy, amido, alkylamido, and dialkylamido;X is selected from C₃-C₈ alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl, optionally substituted heterocycloalkylalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted heteroaryl and optionally substitutedheteroarylalkyl;Y is a bond or a divalent linker group selected from —CH₂—, —O—, —SO₂—,—CH₂O—, —OCH₂— and —CH₂CH₂— with the rightmost radical of the Y groupconnected to the Z substituent;Z is optionally substituted heteroaryl;R_(1a) is selected from hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted alkoxyalkyl with the provisothat when R_(1a) is not hydrogen, R_(1b) is hydrogen or that when R_(1b)is absent, R_(1a) must be hydrogen;R_(1b) is selected from hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted alkoxyalkyl with the provisothat when R_(1b) is not hydrogen, R_(1a) is hydrogen;Each R₂ is independently selected from hydrogen, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted alkoxyalkyl with the provisothat when two R₂ are present, at least one R₂ is hydrogen;R₃ and R₄ are independently selected from hydrogen, C₁-C₄ alkyl, CF₃ andoptionally substituted cycloalkyl with the proviso that at least one R₃or R₄ group must be hydrogen;R₅ is selected from alkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl and optionally substituted alkoxyalkyl;R₇ is selected from hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl andoptionally substituted alkoxyalkyl; andn is independently selected from 1 and 2.In some embodiments, alkyl groups are fully saturated whether present ontheir own or as part of another group (e.g., alkylamino).In certain embodiments, substituent groups are not further substituted.In various embodiments, any group that is defined as being optionallysubstituted is independently singly or multiply substituted.In various embodiments, any group that is defined as being optionallysubstituted not substituted.In one embodiment, a compound of Formula (I) is selected.In another embodiment, a compound of Formula (II) is selected.In another embodiment, a compound of Formula (III) is selected.In one embodiment, alkyl groups are fully saturated whether present ontheir own or on another group.In a further embodiment, HET is selected from Formulas A7, A8, A14, A15,A19, A25, A29, A30, A31, A32, and A38.In a further embodiment, HET is selected from Formulas A7, A8, A25, A29,A30, A31, A32, and A38.In another embodiment, HET is selected from Formulas A7, A8, A25, A29,A30 and A38.In another embodiment, HET is selected from Formulas A7, A8, All A18,A25, A29, and A30.In one embodiment, HET is selected from Formulas A1, A2, A7, A8, A14,A15 and A19.In another embodiment, HET is selected from Formulas A6, A9 A10, A20 andA24.In an additional embodiment, HET is selected from Formulas A1, A2, A7and A8.In another embodiment, HET is selected from Formulas A22, A23, A25 andA26.In another embodiment, HET is selected from Formulas A29, A30, A31 andA32.In another embodiment, HET is selected from Formulas A7, A8, A29 andA30.In a further embodiment, HET is selected from Formulas A7, A8, A29 andA31.In another embodiment, HET is selected from Formulas A29, A31 and A38.In another embodiment, HET is selected from Formulas A25, A29 and A38.In another embodiment, HET is selected from Formulas A25, A29 and A30.In another embodiment, HET is selected from Formulas A25 and A38.In another embodiment, HET is selected from Formulas A7 and A8.In another embodiment, HET is selected from Formulas A25 and A26.In another embodiment, HET is selected from Formulas A29 and A30.In another embodiment, HET is selected from Formulas A29 and A31.In a further embodiment, HET is selected from Formulas A31 and A32.In another embodiment, HET is Formula A1.In another embodiment, HET is Formula A2.In another embodiment, HET is Formula A6.In another embodiment, HET is Formula A7.In another embodiment, HET is Formula A8.In another embodiment, HET is Formula A10.In another embodiment, HET is Formula A11.In another embodiment, HET is Formula A12.In another embodiment, HET is Formula A13.In another embodiment, HET is Formula A14.In another embodiment, HET is Formula A15.In another embodiment, HET is Formula A16.In another embodiment, HET is Formula A17.In another embodiment, HET is Formula A18.In another embodiment, HET is Formula A19.In another embodiment, HET is Formula A20.In another embodiment, HET is Formula A21.In another embodiment, HET is Formula A22.In another embodiment, HET is Formula A23.In another embodiment, HET is Formula A24.In another embodiment, HET is Formula A25.In another embodiment, HET is Formula A26.In another embodiment, HET is Formula A29.In another embodiment, HET is Formula A30.In another embodiment, HET is Formula A31.In another embodiment, HET is Formula A32.In another embodiment, HET is Formula A38.In one embodiment, W is selected from nitro, carboxy, amido, alkylamido,and dialkylamido.In another embodiment, W is selected from amino, alkylamino anddialkylamino.In a further embodiment, W is selected from halogen, cyano and alkoxy.In another embodiment, W is selected from halogen and cyano.In another embodiment, W is halogen.In another embodiment, W is cyano.In another embodiment, W is alkoxy.In one embodiment, X is selected from C₃-C₈ alkyl, cycloalkyl andcycloalkylalkyl.In a further embodiment X is selected from cycloalkyl andcycloalkylalkyl. Examples include, but are not limited to, cyclohexyland cyclohexylmethyl.In another embodiment X is C₃-C₈ alkyl. Examples include, but are notlimited to, isopropyl, t-butyl and isopentyl.In an additional embodiment, X is heterocycloalkyl.In a further embodiment X is heterocycloalkyl having only 6 ring atoms.Examples include, but are not limited to, morpholinyl, piperidinyl,piperazinyl N-Me-piperazinyl and pyranyl.In another embodiment X is heterocycloalkyl having only 5 ring atoms.Examples include, but are not limited to, tetrahydrofuranyl andpyrrolidinyl.In another embodiment, X is a heterocycloalkyl group selected fromFormulas B1-B16 depicted below:

wherein R₆ is selected from hydrogen and C₁-C₆ alkyl, C₃-C₆ cycloalkyland C₃-C₆ cycloalkylalkyl, all of which can be optionally substituted.In another embodiment X is selected from morpholinyl, pyranyl andtetrahydrofuranyl.In another embodiment X is selected from morpholinyl (having formula B1)and 4-pyranyl (having Formula B2).In another embodiment X is heteroaryl.In another embodiment, X is selected from a monocyclic aromatic ringhaving 5 ring atoms selected from C, O, S and N provided the totalnumber of ring heteroatoms is less than or equal to four and where nomore than one of the total number of heteroatoms is oxygen or sulfur,and a monocyclic aromatic ring having 6 atoms selected from C and Nprovided that not more than 3 ring atoms are N, and where said ring maybe optionally and independently substituted with up to two groupsselected from C₁-C₄ alkyl, cycloalkyl, cycloalkyloxy, C₁-C₄ alkoxy, CF₃,carboxyl, alkoxyalkyl, C₁-C₄ cycloalkylalkoxy, amino, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen,cyano, and nitro. Examples include but are not limited to 1H-pyrrolyl,furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl,1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl,1,2,3,5-thiatriazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.In a further embodiment, X is a monocyclic aromatic ring having 6 ringatoms selected from C and N provided that not more than 3 ring atoms areN, and where said ring may be optionally and independently substitutedwith up to two groups selected from C₁-C₄ alkyl, cycloalkyl,cycloalkyloxy, C₁-C₄ alkoxy, CF₃, carboxyl, alkoxyalkyl, C₁-C₄cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido,dialkylamido, thioalkyl, halogen, cyano, and nitro. Examples include butare not limited to 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.In a further embodiment, X is a monocyclic aromatic ring having 5 ringatoms selected from C, O, S, and N, provided the total number of ringheteroatoms is less than or equal to four and where no more than one ofthe total number of heteroatoms is oxygen or sulfur and where said ringmay be optionally and independently substituted with up to two groupsselected from C₁-C₄ alkyl, cycloalkyl, cycloalkyloxy, C₁-C₄ alkoxy, CF₃,carboxyl, alkoxyalkyl, C₁-C₄ cycloalkylalkoxy, amino, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen,cyano, and nitro. Examples include but are not limited to 1H-pyrrolyl,furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl,1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl,1,2,3,5-thiatriazolyl.In a further embodiment, X is selected from 2-pyridinyl, 3-pyridinyl and4-pyridinyl optionally substituted with one group selected from C₁-C₄alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C₁-C₄ alkoxy,CF₃, amino, alkylamino, dialkylamino, thioalkyl, halogen or cyano.In a further embodiment, X is 3-pyridinyl optionally substituted withone group selected from C₁-C₄ alkyl, cyclopropyl, cyclopropyloxy,cyclopropylmethyl, C₁-C₄ alkoxy, CF₃, amino, alkylamino, dialkylamino,thioalkyl, halogen or cyano.In a further embodiment, X is 4-pyridinyl optionally substituted withone group selected from C₁-C₄ alkyl, cyclopropyl, cyclopropyloxy,cyclopropylmethyl, C₁-C₄ alkoxy, CF₃, amino, alkylamino, dialkylamino,thioalkyl, halogen or cyano.In a further embodiment, X is selected from 3-pyridinyl and 4-pyridinyl.In a further embodiment, X is 3-pyridinyl.In another embodiment, X is 2-methoxy-5-pyridinyl.In a further embodiment, X is 4-pyridinyl.In another embodiment, X is 2-methoxy-4-pyridinyl.In another embodiment X is a heterobicyclic ring system.In another embodiment X is a heterobicyclic ring system where one ringis aromatic.In a further embodiment, X is a heterobicyclic ring system where bothrings are aromatic.In another embodiment, X is a heterobicyclic ring system containingexactly 9 ring atoms.In another embodiment, X is a heterobicyclic ring system containingexactly 10 ring atoms.In another embodiment X is selected from benzo[d]oxazoyl,benzo[c][1,2,5] oxadiazyl, benzo[c][1,2,5]thiadiazolyl,benzo[d]isoxazolyl, 1H-benzo[d]imidazoyl, benzo[d]thiazoyl,benzo[c]isothiazolyl, benzo[d]isothiazolyl, benzo[c]isoxazolyl,imidazo[1,2-a]pyridinyl and imidazo[1,5-a]pyridinylIn another embodiment X is selected from benzo[c][1,2,5]oxadiazyl andbenzo[c][1,2,5]thiadiazolyl.In a further embodiment, X is selected from benzo[d]oxazoyl,1H-benzo[d]imidazoyl and benzo[d]thiazoyl.In a further embodiment, X is benzo[d]oxazoyl.In a further embodiment, X is 1H-benzo[d]imidazoyl.In a further embodiment, X is benzo[d]thiazoyl.In another embodiment X is benzo[c][1,2,5]oxadiazoyl.In a further embodiment X is benzo[c][1,2,5]thiadiazolylIn a further embodiment, X is benzo[d]isoxazolyl.In another embodiment, X is benzo[d]isothiazolyl.In another embodiment, X is benzo[c]isothiazolyl.In another embodiment, X is benzo[c]isoxazolyl.In another embodiment, X is imidazo[1,2-a]pyridinyl.In another embodiment, X is imidazo[1,5-a]pyridinyl.In an additional embodiment, X is aryl.In another embodiment, X is selected from phenyl and pyridinyl.In a further embodiment, X is phenyl.In another embodiment, X is phenyl optionally substituted with one ormore substituents selected from F, Cl, CN, NO₂, CF₃, OCF₃, OCHF₂, CH₂CF₃and OMe.In another embodiment, X is restricted phenyl.In a further embodiment, X is selected from a 3,4-disubstituted phenyl,3-substituted phenyl and 4-substituted phenyl.In another embodiment, X is selected from 3,4-disubstituted phenyl and4-substituted phenyl.In another embodiment, X is 3-chloro-4-methoxyphenylIn another embodiment, X is 3-cyano-4-methoxyphenylIn a further embodiment, X is 3-chloro-4-difluoromethoxyphenylIn a further embodiment, X is 3-cyano-4-difluoromethoxyphenylIn an additional embodiment, X is 4-substituted phenyl.In a further embodiment, X is 4-methoxyphenyl.In another embodiment, X is 4-nitrophenyl.In another embodiment, X is 4-chlorophenyl.In another embodiment, X is 4-cyanophenyl.In another embodiment, X is 4-trifluoroethylphenyl.In a further embodiment, X is 4-trifluoromethoxyphenyl.In a further embodiment, X is 3-substituted phenyl.In another embodiment, X is 3-nitrophenyl.In another embodiment, X is 3-trifluoromethoxyphenyl.In a further embodiment, X is 3-methoxyphenyl.In another embodiment, X is 3-chlorophenyl.In another embodiment, X is 3-cyanophenyl.In another embodiment, X is 3-trifluoroethylphenyl.In a further embodiment, X is 3-trifluoromethoxyphenyl.In one embodiment, Y is —CH₂O— or —OCH₂— with the rightmost radicalconnected to the Z substituent.In another embodiment, Y is —CH₂CH₂— with the rightmost radicalconnected to the Z substituent.In an additional embodiment, Y is —CH₂O— with the rightmost radicalconnected to the Z substituent.In a further embodiment, Y is —OCH₂— with the rightmost radicalconnected to the Z substituent.In one embodiment, Z is selected from heteroaryl having only 6 ringatoms and a heterobicyclic ring system.In another embodiment, Z is a heterobicyclic ring system.In another embodiment, Z is a heterobicyclic ring system where one ringis aromatic.In a further embodiment, Z is a heterobicyclic ring system where bothrings are aromatic.In another embodiment, Z is a heterobicyclic ring system containingexactly 9 ring atoms.In another embodiment, Z is a heterobicyclic ring system containingexactly 10 ring atoms.In an additional embodiment, Z is selected from benzimidazolyl,quinolinyl, tetrahydroquinolyl, imidazo[1,2-a]pyridin-2-yl,tetrahydroisoquinolyl, 5-methylpyridin-2-yl, 3,5-dimethylpyridin-2-yl,6-fluoroquinolyl and isoquinolinyl, all of which may be optionallysubstituted with up to 3 substituents independently selected from alkyl,alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy,halogen, alkylsulfonyl and cyano and nitro.In an additional embodiment, Z is selected from benzimidazolyl,quinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and isoquinolinyl,all of which may be optionally substituted with up to 3 substituentsindependently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano andnitro.In an additional embodiment, Z is selected from quinolinyl,imidazo[1,2-a]pyridin-2-yl, 5-methylpyridin-2-yl,3,5-dimethylpyridin-2-yl and 6-fluoroquinolin-2-yl, all of which may beoptionally substituted with up to 3 substituents independently selectedfrom alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.In an additional embodiment, Z is selected from quinolinyl andisoquinolinyl substituted with up to 3 substituents independentlyselected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,cycloalkylalkoxy, halogen, alkylsulfonyl, cyano and nitro.In a further embodiment, Z is selected from 2-quinolinyl and2-benzimidazolyl substituted with up to 3 substituents independentlyselected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.In a further embodiment, Z is 2-quinolinyl substituted with up to 3substituents independently selected from alkyl, alkoxy, cycloalkyl,cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyland cyano and nitro.In a further embodiment, Z is 6-fluoroquinolin-2-yl substituted with upto 3 substituents independently selected from alkyl, alkoxy, cycloalkyl,cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyland cyano and nitro.In a further embodiment, Z is 3,5-dimethylpyridin-2-yl substituted withup to 3 substituents independently selected from alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen,alkylsulfonyl and cyano and nitro.In a further embodiment, Z is 5-methylpyridin-2-yl substituted with upto 3 substituents independently selected from alkyl, alkoxy, cycloalkyl,cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyland cyano and nitro.In an additional embodiment, Z is selected from 2-quinolinyl and2-benzimidazolyl.In an additional embodiment, Z is selected from 2-quinolinyl and5-methylpyridin-2-yl.In an additional embodiment, Z is selected from 2-quinolinyl and3,5-dimethylpyridin-2-yl.In an additional embodiment, Z is selected from 2-quinolinyl and6-fluoroquinolin-2-yl.In an additional embodiment, Z is 2-quinolinyl.In another embodiment, Z is heteroaryl consisting of 6 ring atomsselected from C and N provided the total number of ring nitrogens isless than or equal to two; said ring is optionally substituted with upto 2 substituents independently selected from alkyl, alkoxy, cycloalkyl,cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyland cyano and nitro.In another embodiment, Z is heteroaryl consisting of 6 ring atomsselected from C and N provided the total number of ring nitrogens isless than or equal to two.In a further embodiment, Z is pyridinyl optionally substituted with upto 2 substituents independently selected from alkyl, alkoxy, cycloalkyl,cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen,alkylsulfonyl, cyano and nitro.In a further embodiment, Z is 2-pyridinyl optionally substituted with upto 2 substituents independently selected from alkyl, alkoxy, cycloalkyl,cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyland cyano and nitro.In a further embodiment, any Z is substituent may be unsubstituted.In one embodiment, R_(1a) is selected from cycloalkyl and alkyl with theproviso that R_(1b) is hydrogen.In another embodiment, R_(1a) is selected from hydrogen and alkyl withthe proviso that R_(1b) is hydrogen when R_(1a) is alkyl.In an additional embodiment, R_(1a) is cycloalkyl with the proviso thatR_(1b) is hydrogen.In another embodiment, R_(1a) is alkyl with the proviso that R_(1b) ishydrogen In another embodiment, R_(1a) is fully saturated C₁-C₄ alkylwith the proviso that R_(1b) is hydrogenIn another embodiment, R_(1a) is hydrogen.In one embodiment, R_(1b) is selected from cycloalkyl and alkyl with theproviso that R_(1a) is hydrogen.In one embodiment, R_(1b) is selected from hydrogen and alkyl with theproviso that R_(1a) is hydrogen when R_(1b) is alkyl.In one embodiment, R_(1b) is selected from hydrogen and fully saturatedC₁-C₄ alkyl with the proviso that R_(1a) is hydrogen when R_(1b) isalkyl.In another embodiment, R_(1b) is cycloalkyl with the proviso that R_(1a)is hydrogen.In a further embodiment, R_(1b) is alkyl with the proviso that R_(1a) ishydrogen.In another embodiment, R_(1b) is hydrogen.In one embodiment, each R₂ is independently selected from hydrogen,alkyl, cycloalkyl and cycloalkylalkyl with the proviso that at least oneR₂ is hydrogen;In another embodiment, each R₂ is independently selected from hydrogen,alkyl and cycloalkyl with the proviso that at least one R₂ is hydrogen;In another embodiment, each R₂ is independently selected from hydrogenand alkyl with the proviso that at least one R₂ is hydrogen.In another embodiment, each R₂ is independently selected from hydrogenand fully saturated C₁-C₄ alkyl with the proviso that at least one R₂ ishydrogen.In an additional embodiment, each R₂ is hydrogen.In one embodiment, R₃ and R₄ are independently selected from hydrogenand cycloalkyl with the proviso that at least one R₃ or R₄ group must behydrogen;In a further embodiment, R₃ and R₄ are independently selected fromhydrogen and C₁-C₄ alkyl with the proviso that at least one R₃ or R₄group must be hydrogen;In a further embodiment, R₃ and R₄ are hydrogen.In one embodiment, R₅ is selected from cycloalkylalkyl and alkoxyalkyl.In an additional embodiment, R₅ is selected from cycloalkyl and alkyl.In another embodiment, R₅ is cycloalkyl.In another embodiment, R₅ is alkyl.In one embodiment n is 1.In another embodiment n is 2.In one embodiment, R₇ is selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl and alkoxyalkyl.In another embodiment, R₇ is selected from alkyl, cycloalkyl,cycloalkylalkyl and alkoxyalkyl.In another embodiment, R₇ is selected from hydrogen, alkyl, cycloalkyland cycloalkylalkyl.In another embodiment, R₇ is selected from alkyl, cycloalkyl andcycloalkylalkyl.In another embodiment, R₇ is selected from cycloalkyl andcycloalkylalkyl.In another embodiment, R₇ is selected from alkyl and cycloalkyl.In another embodiment, R₇ is alkyl.In another embodiment, R₇ is cycloalkyl.In another embodiment, R₇ is cycloalkylalkyl.In a further embodiment, R₇ is hydrogen.Compounds of the disclosure may contain asymmetric centers and exist asdifferent enantiomers or diastereomers or a combination of thesetherein. All enantiomeric, diastereomeric forms of Formulas (I), (II)and (III) are embodied herein.Compounds in the disclosure may be in the form of pharmaceuticallyacceptable salts. The phrase “pharmaceutically acceptable” refers tosalts prepared from pharmaceutically acceptable non-toxic bases andacids, including inorganic and organic bases and inorganic and organicacids. Salts derived from inorganic bases include lithium, sodium,potassium, magnesium, calcium and zinc. Salts derived from organic basesinclude ammonia, primary, secondary and tertiary amines, and aminoacids. Salts derived from inorganic acids include sulfuric,hydrochloric, phosphoric, hydrobromic. Salts derived from organic acidsinclude C₁₋₆ alkyl carboxylic acids, di-carboxylic acids andtricarboxylic acids such as acetic acid, proprionic acid, fumaric acid,maleic acid, succinic acid, tartaric acid, adipic acid and citric acid,and alkylsulfonic acids such as methanesulphonic, and aryl sulfonicacids such as para-tolouene sulfonic acid and benzene sulfonic acid.Compounds in the disclosure may be in the form of a solvate. This occurswhen a compound of Formulas (I) or (II) or (III) has an energeticallyfavorable interaction with a solvent, crystallizes in a manner that itincorporates solvent molecules into the crystal lattice or a complex isformed with solvent molecules in the solid or liquid state. Examples ofsolvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, andacetone.Compounds in the disclosure may exist in different crystal forms knownas polymorphs. Polymorphism is the ability of a substance to exist intwo or more crystalline phases that have different arrangements and/orconformations of the molecule in the crystal lattice.Compounds in the disclosure may exist as isotopically labeled compoundsof Formulas (I) or (II) or (III) where one or more atoms are replaced byatoms having the same atomic number but a different atomic mass from theatomic mass which is predominantly seen in nature. Examples of isotopesinclude, but are not limited to hydrogen isotopes (deuterium, tritium),carbon isotopes (¹¹C, ¹³C, ¹⁴C) and nitrogen isotopes (¹³N, ¹⁵N). Forexample, substitution with heavier isotopes such as deuterium (²H) mayoffer certain therapeutic advantages resulting from greater metabolicstability which could be preferable and lead to longer in vivo half-lifeor dose reduction in a mammal or human.Prodrugs of compounds embodied by Formulas (I) or (II) or (III) are alsowithin the scope of this disclosure. Particular derivatives of compoundsof Formulas (I) or (II) or (III) which may have little to negligiblepharmacological activity themselves, can, when administered to a mammalor human, be converted into compounds of Formulas (I) or (II) or (III)having the desired biological activity.Compounds in the disclosure and their pharmaceutically acceptable salts,prodrugs, as well as metabolites of the compounds, may also be used totreat certain eating disorders, obesity, compulsive gambling, sexualdisorders, narcolepsy, sleep disorders, diabetes, metabolic syndrome,neurodegenerative disorders and CNS disorders/conditions as well as insmoking cessation treatment.In one embodiment the treatment of CNS disorders and conditions by thecompounds of the disclosure can include Huntington's disease,schizophrenia and schizo-affective conditions, delusional disorders,drug-induced psychoses, panic and obsessive compulsive disorders,post-traumatic stress disorders, age-related cognitive decline,attention deficit/hyperactivity disorder, bipolar disorders, personalitydisorders of the paranoid type, personality disorders of the schizoidtype, psychosis induced by alcohol, amphetamines, phencyclidine, opioidshallucinogens or other drug-induced psychosis, dyskinesia or choreiformconditions including dyskinesia induced by dopamine agonists,dopaminergic therapies, psychosis associated with Parkinson's disease,psychotic symptoms associated with other neurodegenerative disordersincluding Alzheimer's disease, dystonic conditions such as idiopathicdystonia, drug-induced dystonia, torsion dystonia, and tardivedyskinesia, mood disorders including major depressive episodes,post-stroke depression, minor depressive disorder, premenstrualdysphoric disorder, dementia including but not limited to multi-infarctdementia, AIDS-related dementia, and neurodegenerative dementia,In another embodiment, compounds of the disclosure may be used for thetreatment of eating disorders, obesity, compulsive gambling, sexualdisorders, narcolepsy, sleep disorders as well as in smoking cessationtreatment.In a further embodiment, compounds of the disclosure may be used for thetreatment of obesity, schizophrenia, schizo-affective conditions,Huntington's disease, dystonic conditions and tardive dyskinesia.In another embodiment, compounds of the disclosure may be used for thetreatment of schizophrenia, schizo-affective conditions, Huntington'sdisease and obesity.In a further embodiment, compounds of the disclosure may be used for thetreatment of schizophrenia and schizo-affective conditions.In an additional embodiment, compounds of the disclosure may be used forthe treatment of Huntington's disease.In another embodiment, compounds of the disclosure may be used for thetreatment of obesity and metabolic syndrome.Compounds of the disclosure may also be used in mammals and humans inconjuction with conventional antipsychotic medications including but notlimited to Clozapine, Olanzapine, Risperidone, Ziprasidone, Haloperidol,Aripiprazole, Sertindole and Quetiapine. The combination of a compoundof Formula (I) or (II) or (III) with a subtherapeutic dose of anaforementioned conventional antipsychotic medication may afford certaintreatment advantages including improved side effect profiles and lowerdosing requirements.

DEFINITIONS

Alkyl is a linear or branched saturated or unsaturated aliphatic C₁-C₈hydrocarbon which can be optionally substituted with up to 3 fluorineatoms. Unsaturation in the form of a double or triple carbon-carbon bondmay be internal or terminally located and in the case of a double bondboth cis and trans isomers are included. Examples of alkyl groupsinclude but are not limited to methyl, trifluoromethyl, ethyl,trifluoroethyl, isobutyl, neopentyl, cis- and trans-2-butenyl,isobutenyl, propargyl. C₁-C₄ alkyl is the subset of alkyl limited to atotal of up to 4 carbon atoms.In each case in which a size range for the number of atoms in a ring orchain is disclosed, all subsets are disclosed. Thus, C_(x)-C_(y)includes all subsets, e.g., C₁-C₄ includes C₁-C₂, C₂-C₄, C₁-C₃ etc.Acyl is an alkyl-C(O)— group wherein alkyl is as defined above. Examplesof acyl groups include acetyl and proprionyl.Alkoxy is an alkyl-O— group wherein alkyl is as defined above. C₁-C₄alkoxy is the subset of alkyl-O— where the subset of alkyl is limited toa total of up to 4 carbon atoms. Examples of alkoxy groups includemethoxy, trifluoromethoxy, ethoxy, trifluoroethoxy, and propoxyAlkoxyalkyl is an alkyl-O—(C₁-C₄ alkyl)-group wherein alkyl is asdefined above. Examples of alkoxyalkyl groups include methoxymethyl andethoxymethyl.Alkoxyalkyloxy is an alkoxy-alkyl-O— group wherein alkoxy and alkyl areas defined above. Examples of alkoxyalkyloxy groups includemethoxymethyloxy (CH₃OCH₂O—) and methoxyethyloxy (CH₃OCH₂CH₂O—) groups.Alkylthio is alkyl-S— group wherein alkyl is as defined above.Alkylsulfonyl is alkyl-SO₂— wherein alkyl is as defined above.Alkylamino is alkyl-NH— wherein alkyl is as defined above.Dialkylamino is (alkyl)₂-N— wherein alkyl is as defined above.

Amido is H₂NC(O)—

Alkylamido is alkyl-NHC(O)— wherein alkyl is as defined above.Dialkylamido is (alkyl)₂-NC(O)— wherein alkyl is as defined above.Aromatic is heteroaryl or aryl wherein heteroaryl and aryl are asdefined below.Aryl is a phenyl or napthyl group. Aryl groups may be optionally andindependently substituted with up to three groups selected from halogen,CF₃, CN, NO₂, OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl,heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy,—OCH₂CH₂OCH₃, —OC(O)R_(a), —OC(O)OR_(a), —OC(O)NHR_(a), —OC(O)N(R_(a)),—SR_(a), —S(O)R_(a), —NH₂, —NHR_(a), —N(R_(a))(R_(b)), —NHC(O)R_(a),—N(R_(a))C(O)R_(b), —NHC(O)OR_(a), —N(R_(a))C(O)OR_(b),—N(R_(a))C(O)NH(R_(b)), —N(R_(a))C(O)NH(R_(b))₂, —C(O)NH₂, —C(O)NHR_(a),—C(O)N(R_(a))(R_(b)), —CO₂H, —CO₂R_(a), —COR_(a) wherein R_(a) and R_(b)are independently chosen from alkyl, alkoxyalkyl, —CH₂CH₂OH, —CH₂CH₂OMe,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each ofwhich is optionally and independently substituted with up to threegroups selected from only halogen, Me, Et, ^(i)Pr, ^(t)Bu, unsubstitutedcyclopropyl, unsubstituted cyclobutyl, CN, NO₂, NH₂, CF₃, NHMe, NMe₂,OMe, OCF₃, each of which are attached via carbon-carbon orcarbon-nitrogen or carbon-oxygen single bonds; or R_(a) and R_(b) takentogether with the atom(s) to which they are attached form a 5-6 memberedring.Arylalkyl is an aryl-alkyl-group wherein aryl and alkyl are as definedabove.Aryloxy is an aryl-O— group wherein aryl is as defined above.Arylalkoxy is an aryl-(C₁-C₄ alkyl)-O— group wherein aryl is as definedabove.Carboxy is a CO₂H or CO₂R_(c) group wherein R_(c) is independentlychosen from, alkyl, C₁-C₄ alkyl, cycloalkyl, arylalkyl, cycloalkylalkyl,CF₃, and alkoxyalkyl, wherein alkyl is as defined above.Cycloalkyl is a C₃-C₇ cyclic non-aromatic hydrocarbon which may containa single double bond and is optionally and independently substitutedwith up to three groups selected from alkyl, alkoxy, hydroxyl and oxo.Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexanonyl.Cycloalkyloxy is a cycloalkyl-O— group wherein cycloalkyl is as definedabove. Examples include cyclopropyloxy, cyclobutyloxy andcyclopentyloxy. C₃-C₆ cycloalkyloxy is the subset of cycloalkyl-O— wherecycloalkyl contains 3-6 carbon atoms.Cycloalkylalkyl is a cycloalkyl-(C₁-C₄ alkyl)-group. Examples includecyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl andcyclohexylethyl.Cycloalkylalkoxy is a cycloalkyl-(C₁-C₄ alkyl)-O— group whereincycloalkyl and alkyl are as defined above. Examples of cycloalkylalkoxygroups include cyclopropylmethoxy, cyclopentylmethoxy andcyclohexylmethoxy.

Halogen is F, Cl, Br or I.

Heteroaryl is a tetrazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, amono or bicyclic aromatic ring system, or a heterobicyclic ring systemwith one aromatic ring having 5 to 10 ring atoms independently selectedfrom C, N, O and S, provided that not more than 3 ring atoms in anysingle ring are other than C. Examples of heteroaryl groups include butare not limited to thiophenyl, furanyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrazolyl,imidazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, pyrimidinyl, pyrazinyl,indolyl, quinolyl, tetrahydroquinolyl, isoquinolyl,tetrahydroisoquinolyl, indazolyl, benzthiadiazololyl, benzoxadiazolyland benzimidazolyl. Heteroaryl groups may be optionally andindependently substituted with up to 3 substituents independentlyselected from halogen, CF₃, CN, NO₂, OH, alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy,heteroaryl, heteroaryloxy, —OCH₂CH₂OCH₃, —OC(O)R_(a), —OC(O)OR_(a),—OC(O)NHR_(a), —OC(O)N(R_(a)), —SR_(a), —S(O)R_(a), —NH₂, —NHR_(a),—N(R_(a))(R_(b)), —NHC(O)R_(a), —N(R_(a))C(O)R_(b), —NHC(O)OR_(a),—N(R_(a))C(O)OR_(b), —N(R_(a))C(O)NH(R_(b)), —N(R_(a))C(O)NH(R_(b))₂,—C(O)NH₂, —C(O)NHR_(a), —C(O)N(R_(a))(R_(b)), —CO₂H, —CO₂R_(a), —COR_(a)wherein R_(a) and R_(b) are independently chosen from alkyl,alkoxyalkyl, —CH₂CH₂OH, —CH₂CH₂OMe, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, andheterocycloalkylalkyl, each of which is optionally and independentlysubstituted with up to three groups selected from only halogen, Me, Et,^(i)Pr, ^(t)Bu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN,NO₂, NH₂, CF₃, NHMe, NMe₂, OMe, OCF₃, each of which are attached viacarbon-carbon or carbon-nitrogen or carbon-oxygen single bonds; or R_(a)and R_(b) taken together with the atom(s) to which they are attachedform a 5-6 membered ring.Heteroarylalkyl is a heteroaryl-(C₁-C₄ alkyl)-group wherein heteroaryland alkyl are as defined above. Examples of heteroarylalkyl groupsinclude 4-pyridinylmethyl and 4-pyridinylethyl.Heteroaryloxy is a heteroaryl-O group wherein heteroaryl is as definedabove.Heteroarylalkoxy is a heteroaryl-(C₁-C₄ alkyl)-O— group whereinheteroaryl and alkoxy are as defined above. Examples of heteroarylalkylgroups include 4-pyridinylmethoxy and 4-pyridinylethoxy.Heterobicyclic ring system is a ring system having 8-10 atomsindependently selected from C, N, O and S, provided that not more than 3ring atoms in any single ring are other than carbon and provided that atleast one of the rings is aromatic; said bicyclic ring may be optionallyand independently substituted with up to 3 substituents independentlyselected from alkyl, alkoxy, cycloalkyl, C₃-C₆ cycloalkyloxy,cycloalkylalkyl, halogen, nitro, alkylsulfonyl and cyano. Examples of8-10 membered heterobicyclic ring systems include but are not limited to1,5-naphthyridyl, 1,2,3,4-tetrahydro-1,5-naphthyridyl 1,6-naphthyridyl,1,2,3,4-tetrahydro-1,6-naphthyridyl 1,7-naphthyridyl,1,2,3,4-tetrahydro-1,7-naphthyridinyl 1,8-naphthyridyl,1,2,3,4-tetrahydro-1,8-naphthyridyl, 2,6-naphthyridyl, 2,7-naphthyridyl,cinnolyl, isoquinolyl, tetrahydroisoquinolinyl, phthalazyl, quinazolyl,1,2,3,4-tetrahydroquinazolinyl, quinolyl, tetrahydroquinolinyl,quinoxalyl, tetrahydroquinoxalinyl, benzo[d][1,2,3]triazyl,benzo[e][1,2,4]triazyl, pyrido[2,3-b]pyrazyl, pyrido[2,3-c]pyridazyl,pyrido[2,3-d]pyrimidyl, pyrido[3,2-b]pyrazyl, pyrido[3,2-c]pyridazyl,pyrido[3,2-d]pyrimidyl, pyrido[3,4-b]pyrazyl, pyrido[3,4-c]pyridazyl,pyrido[3,4-d]pyrimidyl, pyrido[4,3-b]pyrazyl, pyrido[4,3-c]pyridazyl,pyrido[4,3-d]pyrimidyl, quinazolyl, 1H-benzo[d][1,2,3]triazoyl,1H-benzo[d]imidazoyl, 1H-indazoyl, 1H-indoyl,2H-benzo[d][1,2,3]triazoyl, 2H-pyrazolo[3,4-b]pyridinyl,2H-pyrazolo[4,3-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl,[1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl,benzo[b]thienyl, benzo[c][1,2,5]oxadiazyl, benzo[c][1,2,5]thiadiazolyl,benzo[d]isothiazoyl, benzo[d]isoxazoyl, benzo[d]oxazoyl,benzo[d]thiazoyl, benzofuryl, imidazo[1,2-a]pyrazyl,imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidyl,imidazo[1,2-b]pyridazyl, imidazo[1,2-c]pyrimidyl, imidazo[1,5-a]pyrazyl,imidazo[1,5-a]pyridinyl, imidazo[1,5-a]pyrimidyl,imidazo[1,5-b]pyridazyl, imidazo[1,5-c]pyrimidyl, indolizyl,pyrazolo[1,5-a]pyrazyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[1,5-a]pyrimidyl, pyrazolo[1,5-b]pyridazine,pyrazolo[1,5-c]pyrimidine, pyrrolo[1,2-a]pyrazine,pyrrolo[1,2-a]pyrimidyl, pyrrolo[1,2-b]pyridazyl,pyrrolo[1,2-c]pyrimidyl, 1H-imidazo[4,5-b]pyridinyl,1H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl,1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl,1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl,1H-pyrrolo[3,2-c]pyridinyl, 2H-indazoyl, 3H-imidazo[4,5-b]pyridinyl,3H-imidazo[4,5-c]pyridinyl, benzo[c]isothiazyl, benzo[c]isoxazyl,furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl,furo[3,2-c]pyridiyl, isothiazolo[4,5-b]pyridinyl,isothiazolo[4,5-c]pyridinyl, isothiazolo[5,4-b]pyridinyl,isothiazolo[5,4-c]pyridinyl, isoxazolo[4,5-b]pyridinyl,isoxazolo[4,5-c]pyridinyl, isoxazolo[5,4-b]pyridinyl,isoxazolo[5,4-c]pyridinyl, oxazolo[4,5-b]pyridinyl,oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl,oxazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridiyl,thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl,thiazolo[5,4-c]pyridinyl, thieno[2,3-b]pyridinyl,thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl andthieno[3,2-c]pyridinyl.Heterocycloalkyl is a non-aromatic, monocyclic or bicyclic saturated orpartially unsaturated ring system comprising 5-10 ring atoms selectedfrom C, N, O and S, provided that not more than 2 ring atoms in anysingle ring are other than C. In the case where the heterocycloalkylgroup contains a nitrogen atom the nitrogen may be substituted with analkyl, acyl, —C(O)O-alkyl, —C(O)NH(alkyl) or a —C(O)N(alkyl)₂ group.Heterocycloalkyl groups may be optionally and independently substitutedwith hydroxy, alkyl, cycloalkyl, cycloalkylalkyl and alkoxy groups andmay contain up to two oxo groups. Heterocycloalkyl groups may be linkedto the rest of the molecule via either carbon or nitrogen ring atoms.Examples of heterocycloalkyl groups include tetrahydrofuranyl,tetrahydrothienyl, tetrahydro-2H-pyran, tetrahydro-2H-thiopyranyl,pyrrolidinyl, pyrrolidonyl, succinimidyl, piperidinyl, piperazinyl,N-methylpiperazinyl, morpholinyl, morpholin-3-one, thiomorpholinyl,thiomorpholin-3-one, 2,5-diazabicyclo[2.2.2]octanyl,2,5-diazabicyclo[2.2.1]heptanyl, octahydro-1H-pyrido[1,2-a]pyrazine,3-thia-6-azabicyclo[3.1.1]heptane and 3-oxa-6-azabicyclo[3.1.1]heptanylHeterocycloalkylalkyl is a heterocycloalkyl-(C₁-C₄ alkyl)-group whereinheterocycloalkyl is as defined above.Heterocycloalkyloxy is a heterocycloalkyl-O— group whereinheterocycloalkyl is as defined above.Heterocycloalkylalkoxy is a heterocycloalkyl-(C₁-C₄ alkyl)-O— groupwherein heterocycloalkyl is as defined above.Oxo is a —C(O)— group.Phenyl is a benzene ring which may be optionally and independentlysubstituted with up to three groups selected from halogen, CF₃, CN, NO₂,OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy,alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl,heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH₂CH₂OCH₃,—OC(O)R_(a), —OC(O)OR_(a), —OC(O)NHR_(a), —OC(O)N(R_(a)), —SR_(a),—S(O)R_(a), —NH₂, —NHR_(a), —N(R_(a))(R_(b)), —NHC(O)R_(a),—N(R_(a))C(O)R_(b), —NHC(O)OR_(a), —N(R_(a))C(O)OR_(b),—N(R_(a))C(O)NH(R_(b)), —N(R_(a))C(O)NH(R_(b))₂, —C(O)NH₂, —C(O)NHR_(a),—C(O)N(R_(a))(R_(b)), —CO₂H, —CO₂R_(a), —COR_(a) wherein R_(a) and R_(b)are independently chosen from alkyl, alkoxyalkyl, —CH₂CH₂OH, —CH₂CH₂OMe,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each ofwhich is optionally and independently substituted with up to threegroups selected from only halogen, Me, Et, ^(i)Pr, ^(t)Bu, unsubstitutedcyclopropyl, unsubstituted cyclobutyl, CN, NO₂, NH₂, CF₃, NHMe, NMe₂,OMe, OCF₃, each of which are attached via carbon-carbon orcarbon-nitrogen or carbon-oxygen single bonds; or R_(a) and R_(b) takentogether with the atom(s) to which they are attached form a 5-6 memberedring.Restricted phenyl is a benzene ring which may be optionally andindependently substituted with up to three groups selected from halogen,CF₃, CN, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl,heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH₂CH₂OCH₃,—OC(O)R_(a), —OC(O)OR_(a), —OC(O)N(R_(a)), —N(R_(a))(R_(b)),—NHC(O)R_(a), —N(R_(a))C(O)R_(b), —NHC(O)OR_(a), —N(R_(a))C(O)OR_(b),—C(O)N(R_(a))(R_(b)), —COR_(a) wherein R_(a) and R_(b) are independentlychosen from alkyl, alkoxyalkyl, —CH₂CH₂OH, —CH₂CH₂OMe, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionallyand independently substituted with up to three groups selected from onlyhalogen, Me, Et, ^(i)Pr, ^(t)Bu, unsubstituted cyclopropyl,unsubstituted cyclobutyl, CN, NO₂, NH₂, CF₃, NHMe, NMe₂, OMe, OCF₃, eachof which are attached via carbon-carbon or carbon-nitrogen orcarbon-oxygen single bonds; or R_(a) and R_(b) taken together with theatom(s) to which they are attached form a 5-6 membered ring.Abbreviations used in the following examples and preparations include:

-   -   Ac Acyl (Me-C(O)—)    -   AcN Acetonitrile    -   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   Bn Benzyl    -   Celite® Diatomaceous earth    -   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene    -   DCC N,N′, Dicyclohexylcarbodiimide    -   DCM Dichloromethane    -   DIEA Di-isopropylethyl amine    -   DIPEA Di-isopropylethyl amine    -   DMAP 4-Dimethylaminopyridine    -   DMF Dimethylformamide    -   DMP Dess Martin Periodinane    -   DMSO Dimethyl sulfoxide    -   Dppf 1,4-Bis(diphenylphosphino) ferrocene    -   EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride    -   Et₃N Triethylamine    -   g gram(s)    -   h Hour(s)    -   hr Hour(s)    -   HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HMDS Hexamethyldisilazide    -   HOBt 1-Hydroxybenzotriazole    -   HPLC High Pressure Liquid Chromatography    -   HRMS High resolution mass spectrometry    -   i.v. Intravenous    -   KHMDS Potassium Hexamethydisilazide    -   LDA Lithium Di-isopropylamide    -   m Multiplet    -   m- meta    -   mCPBA meta-chloroperbenzoic acid    -   MEM Methoxyethoxymethyl    -   MeOH Methyl Alcohol or Methanol    -   min Minute(s)    -   mmol millimoles    -   mmole millimoles    -   Ms Mesylate    -   MS Mass Spectrometry    -   MW Molecular Weight    -   NBS N-Bromosuccinamide    -   NCS N-Chlorosuccinamide    -   NIS N-Iodosuccinamide    -   NMR Nuclear Magnetic Resonance    -   NMM N-Methyl Morpholine    -   NMP N-Methyl-2-pyrrolidone    -   o ortho    -   o/n overnight    -   p para    -   PCC Pyridinium Chlorochromate    -   PEPPSI        1,3-Bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridinyl)        palladium(II) dichloride    -   PhNTf₂        1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide    -   POPd Dihydrogen dichlorobis(di-tert-butylphosphinito-kp)        palladate (2-)    -   p.s.i. Pounds per square inch    -   PPA Polyphosphoric acid    -   PPAA 1-Propanephosphonic Acid Cyclic Anhydride    -   PTSA p-Toluenesulfonic acid    -   PyBOP® Benzotriazol-1-yl-oxytripyrrolidinophosphonium        hexafluorophosphate    -   RT (or rt) room temperature (about 20-25° C.)    -   s Singlet    -   sat. Saturated    -   t Triplet    -   TBAF Tetra-butyl ammonium fluoride    -   TEA Triethylamine    -   TFA Trifluoroacetic Acid    -   THF Tetrahydrofuran    -   TLC Thin layer chromatography    -   TMS Trimethylsilyl    -   Tf Triflate    -   Tof-MS Time of Flight Mass Spectrometry    -   Ts Tosylate    -   v/v volume/volume    -   wt/v weight/volume

DETAILED DESCRIPTION OF THE DISCLOSURE

The 5- and 6-membered heterocyclic compounds of Formula (I), (II) or(III) may be prepared from multi-step organic synthesis routes fromcommercially available starting materials by one skilled in the art oforganic synthesis using established organic synthesis procedures.

Compounds of the disclosure of Formula (I), (II) or (III) in whichX=phenyl, heteroaryl or heterocycloalkyl are as described previously andthus having general Formula XIII may be prepared generally as depictedin Scheme 1.

Compounds of the disclosure of Formula (I), (II) or (III) in whichX=phenyl, heteroaryl or heterocycloalkyl are as described previously andthus having general Formula XXIII may be prepared generally as depictedin Scheme 2

Compounds of the disclosure of Formulas (I), (II) or (III) in whichX=aryl, phenyl or heteroaryl are as described previously and thus havinggeneral Formula XXXIV may be prepared generally as depicted in Scheme 3.

Compounds of the disclosure of Formulas (I), (II) or (III) in whichX=heterocycloalkyl are as described previously and thus having generalFormula XLIII may be prepared generally as depicted in Scheme 4:

Compounds of the disclosure of Formulas (I), (II) or (III) in whichX=aryl, phenyl, heteroaryl or heterocycloalkyl are as describedpreviously and thus having general Formula LI may be prepared generallyas depicted in Scheme 5.

Compounds of the disclosure of Formulas (I), (II) or (III) in whichX=phenyl or heteroaryl are as described previously and thus havinggeneral Formula LXIII may be prepared generally as depicted in Scheme 6.

Reactive groups not involved in the above processes can be protectedwith standard protecting groups during the reactions and removed bystandard procedures (T. W. Greene & P. G. M. Wuts, Protecting Groups inOrganic Synthesis, Third Edition, Wiley-Interscience) known to those ofordinary skill in the art. Presently preferred protecting groups includemethyl, benzyl, MEM, acetate and tetrahydropyranyl for the hydroxylmoiety, and BOC, Cbz, trifluoroacetamide and benzyl for the aminomoiety, methyl, ethyl, tert-butyl and benzyl esters for the carboxylicacid moiety

Experimental Procedures HPLC Conditions Condition-A: Column: HypersilBDS C8 250×4.6 mm, 5 um (SHCLO6E001) Mobile Phase AcN (A): 0.1% TFA inWater (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-B: Column: Zobrax SB-C18 250×4.6 mm, 5 um Mobile Phase AcN(A): 0.1% TFA in Water (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-C: Column: Targa C-18 250×4.6 mm, 5 um Mobile Phase AcN (A):0.1% TFA in Water (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-D: Column: Targa C18 250×4.6 mm, 5 um (SHCL-12) Mobile PhaseAcN (A): 5M Ammonium Acetate in Water. (B).

Flow rate: 1.0 ml/min (Gradient

Condition-E: Column: Higgins-C18 250×4.6 mm, 5 um Mobile Phase AcN (A):0.1% TFA in Water (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-F: Column: Chiralpak AD

Mobile Phase: n-Hexane:Ethanol (50:50)Flow rate: 0.6 ml/min (Gradient)

Condition-G: Column: Venusil C8, 250×4.6 mm, 5 um. Mobile Phase AcN (A):0.1% TFA in Water (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-H: Column: Eclipse XDB-C18, 150×4.6 mm, Sum. Mobile Phase:0.1% TFA in Water (A): AcN (B).

Flow rate: 1.5 ml/min (Gradient)

Condition-I: Column: Acquity BEH-C18, (50×2.1 mm, 1.7 um.) Mobile PhaseAcN (B)

Flow rate: 0.5 ml/min (Gradient)

Condition-J: Column: Zobrax C18, (150×4.6 mm, 5 um.) Mobile Phase AcN(A): 0.1% TFA in Water (B).

Flow rate: 1.0 ml/min (Gradient)

Synthesis of3-(Pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)isoxazol-5(2H)-one(Example 1094) Methyl3-hydroxy-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl) propanoate

To a 0° C. stirred solution of ethyl2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (1.0 g, 3.1 mmol) in methanol(10 mL), NaOMe (0.185 g, 3.42 mmol) was added slowly. After stirring for10 minutes, isonicotinaldehyde (0.367 g, 3.42 mmol) was then added andthe reaction mixture was stirred at RT for 16 h. The reaction mixturewas then quenched with cold water; volatiles were concentrated in vacuoand extracted with EtOAc (2×20 mL). The combined organic layers werewashed with water, dried over Na₂SO₄, filtered, and concentrated invacuo to obtain crude product. The crude material was purified viasilica gel column chromatography to afford methyl3-hydroxy-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl) propanoate(1.02 g, 85%) as a solid.

Methyl 3-oxo-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)propanoate

To a stirred solution of3-hydroxy-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl) propanoate(0.5 g, 1.2 mmol) in DCM (10 mL) was added Dess-Martin periodinane(1.024 g, 2.4 mmol) at 0° C. The reaction mixture was stirred at RT for3 h, quenched with a saturated NaHCO₃ solution and extracted with EtOAc(2×30 mL). The combined organic layers were washed with water, brine,dried over Na₂SO₄, filtered and concentrated in vacuo to obtain thecrude product. The crude material was purified via silica gel columnchromatography to afford methyl3-oxo-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl) propanoate(0.4 g, 80%) as a solid.

3-(Pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)isoxazol-5(2H)-one(Example 1094)

To a stirred solution of methyl3-oxo-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl) propanoate(100 mg, 0.24 mmol) in ethanol (0.5 mL), NH₂OH—HCl (0.083 g, 1.2 mmol)and TEA (0.101 mL, 0.72 mmol) were added to the mixture dropwise. Thereaction mixture was then refluxed for 16 h and then concentrated invacuo to obtain the crude product. The crude material was washed withwater and EtOAc to afford3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)isoxazol-5(2H)-one(30 mg, 31%) as a solid. ¹H NMR (500 MHz, d₆-DMSO): δ 8.68-8.61 (m, 2H),8.42-8.38 (m, 1H), 8.02-7.94 (m, 2H), 7.79-7.74 (m, 1H), 7.69-7.64 (m,1H), 7.62-7.58 (m, 1H), 7.42-7.38 (m, 2H), 7.19-7.14 (m, 2H), 7.01-6.92(m, 2H), 5.38 (s, 2H), 3.59 (s, 1H). MS: M⁺H: m/z=396.1. HPLC: 91%,(Condition-B).

Synthesis of5-(Pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one(Example 1096)5-(Pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one(Example 1096

To a stirred solution of methyl3-oxo-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)propanoate (0.2g, 0.48 mmol) in ethanol (5 mL), NH₂NH₂.H₂O (0.12 g, 2.42 mmol) and TEA(0.146 g, 1.45 mmol) were added dropwise at RT. The reaction mixture wasthen refluxed for 16 h and then concentrated in vacuo to obtain crudeproduct. The crude material was washed with water (5 mL) and ether (5mL) to afford5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one(70 mg, 37%) as a white solid. ¹H NMR (500 MHz, d₆-DMSO): δ 9.12 (bs,1H), 8.38 (d, J=7.2 Hz, 2H), 8.02-7.96 (m, 3H), 7.76 (t, J=7.6 Hz, 2H),7.64-7.56 (m, 3H), 7.16 (d, J=7.2 Hz, 2H), 6.96 (d, J=7.2 Hz, 2H), 5.38(s, 2H), 3.21 (s, 1H). MS: M⁺H: m/z=395.1 and HPLC: 80%, (Condition-C).

Synthesis of2-methyl-5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one(Example 1097)2-Methyl-5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one(Example 1097)

Following the procedure for the preparation of5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-oneusing methyl hydrazine provided the title compound. Yield: 15%. ¹H NMR(500 MHz, d₆-DMSO): δ 8.44-8.36 (m, 2H), 8.04-7.96 (m, 2H), 7.82-7.74(m, 2H), 7.72-7.56 (m, 2H), 7.38-7.22 (m, 1H), 7.18-7.12 (m, 2H),7.10-7.06 (m, 1H), 7.01-6.98 (m, 2H), 5.36 (s, 2H), 3.69 (s, 1H), 3.59(s, 3H). MS: M⁺H: m/z=409.1.

Synthesis of 4-(Pyridin-3-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 1098) 2-Bromo-1-(pyridin-4-yl)ethanonehydrobromide

To a stirred solution of 1-(pyridin-4-yl)ethanone (10 g, 0.08 mol) inCCl₄ (150 mL) Br₂ (3.99 mL, 0.02 mol) was added dropwise at 0° C. Thereaction mixture was then refluxed for 1 h, filtered and dried in vacuoto afford 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (22 g, 94%) as asolid.

Ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (10 g, 0.05mol) in acetonitrile (150 mL) were added K₂CO₃ (23 g, 0.16 mol) and2-(chloromethyl) quinoline (14.2 g, 0.06 mol) under an inert atmosphere.The reaction mixture was then heated at 80° C. for 16 h, diluted withwater (50 mL) and extracted with EtOAc (3×100 mL). The combined organiclayers were washed with water (100 mL) and brine (100 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo to afford ethyl2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (19 g, 95%) as an oil.

2-(4-(Quinolin-2-ylmethoxy)phenyl)acetic acid

To a stirred solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate(20 g, 0.05 mol) in MeOH (200 mL), a solution of KOH (12.6 g, 0.22 mol)in water (50 mL) was added dropwise and the reaction mixture was stirredfor 1 h at RT. The methanol was then removed and the reaction mixturewas washed with EtOAc (2×100 mL) and acidified to pH˜3 with 1 N HCl at0° C. The precipitated solid was then filtered and dried to afford2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (15 g, 92%) as a whitesolid.

2-Oxo-2-(pyridin-3-yl)ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate

To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (2.0 g,0.006 mol) in acetonitrile (200 mL) were added TEA (1.74 mL, 0.01 mol),and 2-bromo-1-(pyridin-3-yl)ethanone (3.42 g, 0.017 mol) under an inertatmosphere. The reaction mixture was then stirred at RT for 16 h,concentrated in vacuo and the residue was extracted with EtOAc (2×100mL). The combined organic layers were washed with water, dried overNa₂SO₄, filtered, and concentrated in vacuo to obtain the crude product.The crude material was purified via silica gel column chromatography toafford 2-oxo-2-(pyridin-3-yl)ethyl2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (1.5 g, 54%) as a solid.

4-(Pyridin-3-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one(Example 1098)

To a 0° C. solution of 2-oxo-2-(pyridin-3-yl)ethyl2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (200 mg, 0.48 mmol) in DMF (5mL) was added NaH (58 mg, 1.21 mmol). The reaction mixture was thenstirred at RT for 1 h, quenched with ice, and extracted with EtOAc (2×30mL). The combined organic layers were washed with water, dried overNa₂SO₄, filtered, and concentrated in vacuo to obtain the crude product.The crude material was purified via silica gel column chromatography toafford 4-(pyridin-3-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (10 mg, 5%) as a solid. ¹H NMR (500 MHz, d₆-DMSO): δ8.41 (d, J=7.2 Hz, 1H), 8.04-7.96 (m, 2H), 7.82-7.76 (m, 2H), 7.70-7.58(m, 3H), 7.20-7.12 (m, 3H), 7.02-6.96 (m, 3H), 5.35 (s, 2H), 3.52 (s,2H). MS: M⁺H: m/z=395.2 and HPLC: 89%, (Condition-C).

Synthesis of 4-(Pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 37), Route A 2-(4-(Benzyloxy)phenyl)acetic acid

To a stirred solution of ethyl 2-(4-(benzyloxy)phenyl)acetate (20 g,0.07 mol) in EtOH (300 mL) was added a solution of KOH (20.7 g, 0.37mol) in water (100 mL) at RT. The reaction mixture was then stirred foradditional 1 h at RT and then concentrated in vacuo. The residue wasacidified to pH˜2 using 2 N HCl and extracted with EtOAc (3×200 mL). Thecombined organic layers were washed with water, dried over Na₂SO₄,filtered, and concentrated in vacuo to afford2-(4-(benzyloxy)phenyl)acetic acid (19 g, 98%) as a solid.

2-Bromo-1-(pyridin-4-yl)ethanone hydrobromide

To a stirred solution of 1-(pyridin-4-yl)ethanone (10 g, 0.08 mol) inCCl₄ (150 mL), Br₂ (3.99 mL, 0.02 mol) was added dropwise at 0° C. Thereaction mixture was then refluxed for 1 h, filtered, and dried in vacuoto afford 2-bromo-1-(pyridin-4-yl)ethanone hydro bromide (22 g, 94%) asa solid.

2-Oxo-2-(pyridin-4-yl)ethyl 2-(4-(benzyloxy)phenyl)acetate

To a 10° C. stirred solution of 2-(4-(benzyloxy)phenyl)acetic acid (5.0g, 0.02 mol) in MeOH (50 mL) was added a solution of potassiumtert-butoxide (2.43 g, 0.02 mol) in MeOH (50 mL) under an inertatmosphere. The reaction mixture was stirred for 1 h, concentrated invacuo and the residue was dissolved in DMF (30 mL). Potassiumtert-butoxide (3.6 g, 0.03 mmol) was then added followed by2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (10.3 g, 0.05 mol), andthe reaction mixture at RT. The reaction mixture was then stirred for anadditional 16 h at RT, quenched with water, stirred for an additional 10min and the precipitated solid was filtered. The crude solid wasdissolved in EtOAc (200 mL) and washed with water, dried over Na₂SO₄,filtered and concentrated in vacuo to afford 2-oxo-2-(pyridin-4-yl)ethyl2-(4-(benzyloxy)phenyl)acetate (3.6 g, 48%) as a solid.

3-(4-(Benzyloxy)phenyl)-4-(pyridin-4-yl) furan-2(5H)-one

To a stirred solution of 2-oxo-2-(pyridin-4-yl)ethyl2-(4-(benzyloxy)phenyl)acetate (1.8 g, 0.004 mol) in acetonitrile (50mL) was added triethylamine (10 mL, 0.07 mol) under an inert atmosphere.The reaction mixture was then refluxed for 2 h, concentrated in vacuo,and the residue was dissolved in EtOAc (100 mL). The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated in vacuoto yield the crude product. The crude material was purified via silicagel column chromatography to afford3-(4-(benzyloxy)phenyl)-4-(pyridin-4-yl) furan-2(5H)-one (140 mg, 8%).

3-(4-hydroxyphenyl)-4-(pyridin-4-yl) furan-2(5H)-one

A mixture of 3-(4-(benzyloxy)phenyl)-4-(pyridin-4-yl) furan-2(5H)-one(1.0 g, 0.002 mol) in 33% HBr/AcOH (50 mL) was refluxed for 3 h. Thereaction mixture was quenched with a saturated NaHCO₃ solution andextracted with EtOAc (2×50 mL). The combined organic layers were washedwith water, dried over Na₂SO₄, filtered, and concentrated in vacuo toafford 3-(4-hydroxyphenyl)-4-(pyridin-4-yl) furan-2(5H)-one (0.7 g,95%).

4-(Pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one(Example 37)

To a stirred solution of 3-(4-hydroxyphenyl)-4-(pyridin-4-yl)furan-2(5H)-one (700 mg, 2.76 mmol) in DMF (10 mL) was added K₂CO₃(763.6 mg, 5.5 mmol) followed by 2-(chloromethyl)quinoline (711 mg, 3.32mmol). The reaction mixture was then heated at 80° C. for 2 h, quenchedwith cold water, and extracted with EtOAc (2×25 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to obtain the crude product. The crude materialwas purified via silica gel column chromatography to afford4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one (190mg, 19%) as a solid. ¹H NMR (500 MHz, d₆-DMSO): δ 8.61 (d, J=7.7 Hz,2H), 8.42 (d, J=7.1 Hz, 1H), 8.04-7.96 (m, 2H), 7.81-7.76 (m, 1H), 7.65(d, J=7.4 Hz, 1H), 7.60-7.54 (m, 1H), 7.44-7.36 (m, 4H), 7.11 (d, J=7.2Hz, 2H), 5.40 (s, 2H), 5.34 (s, 2H). MS: M⁺H: m/z=395.1 and HPLC: 95%,(Condition-H).

Synthesis of 4-(Pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 37), Route B Ethyl2-(4-(quinolin-2-ylmethoxy)phenyl)acetate

To a stirred solution of compound ethyl 2-(4-hydroxyphenyl)acetate (30g, 0.16 mol) in acetonitrile (300 mL) was added K₂CO₃ (114.9 g, 0.83mol) and 2-(chloromethyl) quinoline (42.7 g, 0.19 mol) at RT. Thereaction mixture was refluxed for 16 h, filtered and the resulting solidresidue was extracted with EtOAc (2×100 mL). The combined organic layerswere washed with water, dried over Na₂SO₄ and concentrated in vacuo toafford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (50 g, 93%) as asolid.

2-(4-(Quinolin-2-ylmethoxy)phenyl)acetic acid

To a solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (8 g,0.02 mol) in MeOH: THF (300 mL; 1:1) was added LiOH.H₂O (5.21 g, 0.124mol). The reaction mixture was stirred at RT for 1 h and thenconcentrated in vacuo to obtain the crude compound. The crude materialwas acidified with HCl (1N), filtered and dried in vacuo to afford2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (7.0 g, 95%) as a solid.

4-(Pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one(Example 37)

To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (3.0 g,0.01 mol) in acetonitrile (40 mL) were added TEA (1.3 mL, 0.01 mol) and2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (2.86 g, 0.01 mol) at RTunder an inert atmosphere. The reaction mixture was stirred for 1 h andthen cooled to 0° C. DBU (46.6 g, 0.03 mol) was then added and thereaction mixture was stirred for 2 h at 0° C. and quenched with HCl (1N). The aqueous layer was basified with a NaHCO₃ solution and extractedwith DCM (2×50 mL). The combined organic layers were washed with water,dried over Na₂SO₄ and concentrated in vacuo to obtain the crude product.The crude material was purified via silica gel column chromatographyeluting with 25% EtOAc in hexanes to afford4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one (600mg, 15%) as a solid.

Synthesis of1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one(Example 94)(Z)-4-Hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)but-2-enamide

A solution of 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (1.0 g, 0.002 mol) and MeNH₂ in MeOH (25 mL) wasrefluxed for 1 h. The reaction mixture was concentrated in vacuo toafford(Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)but-2-enamide (920 mg, 86%) as a solid.

1-Methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one(Example 94)

To a 0° C. solution of(Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)but-2-enamide (430 mg, 1.01 mmol) in 1:1 ether:DCM (20 mL), PBr₃ (0.114mL, 1.21 mol) was added. The reaction mixture was stirred at RT for 2 h,diluted with DCM and basified with a NaHCO₃ solution. The organic layerwas separated, washed with water, dried over Na₂SO₄ and concentrated invacuo to obtain the crude product. The crude material was purified viasilica gel column chromatography to afford1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one(350 mg, 85%) as a solid. ¹H NMR (500 MHz, CD₃OD): δ 8.81 (d, J=7.8 Hz,2H), 8.24-8.19 (m, 2H), 8.11-7.94 (m, 3H), 7.85-7.80 (m, 1H), 7.59 (d,J=7.2 Hz, 2H), 7.44 (s, 2H), 7.21 (d, J=7.2 Hz, 2H), 5.61 (s, 2H), 3.38(s, 2H), 3.09 (s, 3H). MS: M⁺H: m/z=408.2. HPLC: 89%, (Condition-B).

Synthesis of4-morpholino-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example1085) 2-((4-Bromophenoxy)methyl) quinoline

To a stirred solution of 4-bromophenol (10 g, 0.057 mol) and 2-(chloromethyl)quinoline (15.4 g, 0.063 mol) in AcN (25 mL) was added K₂CO₃ (24g, 0.17 mol). The reaction mixture was refluxed for 3 h, filtered andthe filtrate was concentrated in vacuo. The residue was diluted withwater and extracted with EtOAc (2×200 mL). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo toobtain 2-((4-bromophenoxy)methyl) quinoline (9 g, 50%) as a solid.

2-((4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline

To a stirred solution of 2-((4-bromophenoxy)methyl) quinoline (3 g,0.008 mol) in dioxane (20 mL) was added bispinacolato diborane (2.7 g,0.010 mol) followed by potassium acetate (2.59 g, 0.026 mol) at roomtemperature under a N₂ atmosphere. The reaction mixture was stirred for10 minutes and then P(Cy)₃ (0.18 g, 0.65 mmol) followed by Pd(dba)₂(0.32 g, 0.35 mmol) were added to reaction mixture. The reaction mixturewas then refluxed for 1 h, diluted with water and extracted with EtOAc(2×100 mL). The combined organic layers were dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo to afford 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl) quinoline (2.5g, 74%) as a solid.

3,4-Dibromofuran-2(5H)-one

To a stirred solution of 3,4-dibromo-5-hydroxyfuran-2(5H)-one (3.0 g,0.011 mol) in MeOH (27 mL) was added NaBH₄ (660 mg, 0.017 mol) at 0° C.under a N₂ atmosphere. The reaction mixture was stirred for 30 minutesand then a solution of H₂SO₄ (1.8 g) in MeOH (9 mL) was added. Thereaction mixture was stirred for an additional 1 h, concentrated invacuo and the residue was dissolved in DCM (100 mL). The organic layerwas then washed with water, dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo to afford 3,4-dibromofuran-2(5H)-one (2.6 g, 93%)as a solid.

3-Bromo-4-morpholinofuran-2(5H)-one

To a stirred solution of 3,4-dibromofuran-2(5H)-one (1 g, 0.004 mol) inDMF (10 mL) was added Cs₂CO₃ (1.34 g, 0.004 mol) followed by morpholine(360 mg, 0.004 mol) at room temperature under a N₂ atmosphere. Thereaction mixture was then stirred for 30 minutes, quenched with icewater and extracted with EtOAc (2×50 mL). The combined organic layerswere washed with water, dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo to afford 3-bromo-4-morpholinofuran-2(5H)-one(0.87 g, 85%) as a solid.

4-Morpholino-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example1085)

To a stirred solution of 3-bromo-4-morpholinofuran-2(5H)-one (300 mg,1.20 mmol) in 2:1 toluene/H₂O (8 mL) were added 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (480mg, 1.33 mmol), Cs₂CO₃ (1.54 g, 4.23 mmol) and Pd(dppf)Cl₂ (197.5 mg,0.24 mmol). The reaction mixture was then refluxed for 4 h, filtered andthe filtrate was partitioned between water and EtOAc. The organic layerwas separated, washed with water, dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The crude material was purified via silicagel column chromatography eluting with 40% EtOAc in hexanes to afford4-morpholino-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (50 mg,10%) as a solid. ¹H NMR (500 MHz, d₆-DMSO): δ 8.42 (d, J=7.6 Hz, 1H),8.04-7.96 (m, 2H), 7.82-7.76 (m, 1H), 7.70-7.67 (m, 1H), 7.65-7.59 (m,1H), 7.17 (d, J=7.2 Hz, 2H), 7.05 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 4.91(s, 2H), 3.60 (bs, 4H), 3.19 (bs, 4H). MS: M⁺H: m/z=403.1; M⁺Na:m/z=425.2 HPLC: 90%, (Condition-J).

Synthesis of 3-(4-methoxyphenyl)-4-(4(2-(quinolin-2-yl)ethyl)phenyl)furan-2(5H)-one (Example 14) Ethyl 2-(4-methoxyphenyl)acetate

To a solution of ethyl 2-(4-hydroxyphenyl)acetate (15 g, 0.09 mmol) inacetonitrile (100 mL) were added anhydrous K₂CO₃ (27.23 g, 0.19 mol)followed by Me₂SO₄ (14.94 g, 0.11 mol) at RT. The reaction mixture wasthen refluxed for 5 h, filtered through a pad of Celite® and thefiltrate was concentrated in vacuo. The residue was dissolved in EtOAc(300 mL). The organic layer was then washed with water, dried overNa₂SO₄ and concentrated in vacuo to afford ethyl2-(4-methoxyphenyl)acetate (16 g, 84%) as a solid.

2-(4-Methoxyphenyl)acetic acid

To a solution of ethyl 2-(4-methoxyphenyl)acetate (5.0 g, 0.025 mol) in2:2:1 MeOH: THF: H₂O (50 mL) was added LiOH.H₂O (5.14 g, 0.128 mol). Thereaction mixture was stirred at RT for 16 h and concentrated in vacuo toobtain the crude product. The crude material was acidified with HCl (1N)to pH 2 and then the product was extracted with EtOAc (2×100 mL). Thecombined organic layers were washed with water, dried over Na₂SO₄, andconcentrated in vacuo to afford 2-(4-methoxyphenyl)acetic acid (4.05 g,94%) as a solid.

1-(4-(Benzyloxy)phenyl)ethanone

To a solution of 1-(4-hydroxyphenyl)ethanone (10 g, 0.07 mol) in DMF (15mL), were added anhydrous K₂CO₃ (20.3 g, 0.14 mol) and benzyl chloride(11.16 g, 0.08 mmol). The reaction mixture was then stirred at RT for 16h, quenched with ice, and a solid was precipitated. The obtained solidresidue was filtered and dried in vacuo to afford1-(4-(benzyloxy)phenyl)ethanone (14.7 g, 89%) as a solid.

1-(4-(Benzyloxy)phenyl)-3-phenylpropan-1-one

To a solution of 1-(4-(benzyloxy)phenyl)ethanone (5.0 g, 0.02 mol) inMeOH (120 mL) was added a solution of Br₂ (4.22 g, 0.026 mol) in MeOH(13 mL). The reaction mixture was stirred at RT for 3 h and thenconcentrated in vacuo. The residue was then treated with HCl (1N, 20mL), quenched with ice, and the resulting solid precipitate was filteredand dried in vacuo to afford1-(4-(benzyloxy)phenyl)-3-phenylpropan-1-one (6 g, 89%) as a whitesolid.

2-(4-(Benzyloxy)phenyl)-2-oxoethyl 2-(4-methoxyphenyl)acetate

To a stirred solution of 2-(4-methoxyphenyl)acetic acid (3 g, 0.01 mol)in acetonitrile (60 mL) were added TEA (16.5 mL, 0.129 mol) and1-(4-(benzyloxy)phenyl)-3-phenylpropan-1-one (6.6 g, 0.02 mol). Thereaction mixture was stirred at RT for 16 h, concentrated in vacuo andthe resulting residue was extracted with EtOAc (2×100 mL). The combinedorganic layers were washed with water, dried over Na₂SO₄ andconcentrated in vacuo to afford 2-(4-(benzyloxy)phenyl)-2-oxoethyl2-(4-methoxyphenyl)acetate (5 g, 71%) as a brown solid.

4-(4-(Benzyloxy)phenyl)-3-(4-methoxyphenyl) furan-2(5H)-one

To a 0° C. solution of 2-(4-(benzyloxy)phenyl)-2-oxo-ethyl2-(4-methoxyphenyl)acetate (3.0 g, 0.007 mol) in DMF (20 mL) was addedNaH (0.96 g, 0.01 mol). The reaction mixture was stirred at RT for 30minutes and quenched with ice to obtain a solid precipitate. The solidprecipitate was filtered and dried in vacuo to afford4-(4-(benzyloxy)phenyl)-3-(4-methoxyphenyl) furan-2(5H)-one (2.4 g, 84%)as a solid.

4-(4-Hydroxyphenyl)-3-(4-methoxyphenyl) furan-2(5H)-one

To a 0° C. solution of 4-(4-(benzyloxy)phenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (1.5 g, 0.004 mol) in MeOH (50 mL) was added Pd(OH)₂(150 mg, 1.068 mol) under an inert atmosphere. The reaction mixture wasthen stirred under a hydrogen atmosphere for 2 h at RT, filtered througha pad of Celite® and the filtrate was concentrated in vacuo to afford4-(4-hydroxyphenyl)-3-(4-methoxyphenyl) furan-2(5H)-one (900 mg, 81%) asa solid.

3-(4-Methoxyphenyl)-4-(4-(2-(quinolin-2-yl)ethyl)phenyl) furan-2(5H)-one(Example 14)

To a stirred solution of 4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)furan-2(5H)-one (280 mg, 0.99 mol) in DMF (5 mL) were added K₂CO₃ (274mg, 1.98 mol) and 2-(chloromethyl) quinoline (255 mg, 1.19 mol) at RT.The reaction mixture was then heated at 80° C. for 3 h, quenched withice and then extracted with EtOAc (2×20 mL). The combined organic layerswere washed with water, dried over Na₂SO₄, and concentrated in vacuo toobtain the crude product. The crude material was purified via silica gelcolumn chromatography using 20% ethyl aceate in hexanes to afford3-(4-methoxyphenyl)-4-(4-(2-(quinolin-2-yl)ethyl)phenyl) furan-2(5H)-one(50 mg, 12%) as a yellow solid.

¹H NMR (500 MHz, d₆-DMSO): δ 8.41 (d, J=7.8 Hz, 1H), 8.02-7.98 (m, 2H),7.78 (t, J=7.6 Hz, 1H), 7.68-7.52 (m, 1H), 7.23 (d, J=7.2 Hz, 2H), 7.25(d, J=7.6 Hz, 2H), 7.10 (d, J=7.6 Hz, 2H), 6.98 (d, J=7.2 Hz, 2H), 5.40(s, 2H), 5.25 (s, 2H), 3.79 (s, 3H). MS: M⁺H: m/z=424.2. HPLC: 97%,(Condition-H).

Synthesis of3-(4-methoxyphenyl)-4-(4-((6-methylpyridin-2-yl)methoxy)phenyl)furan-2(5H)-one(Example 1095) 2,6-Dimethylpyridine 1-oxide

To a 0° C. solution of 2,6-dimethylpyridine (1.0 g, 0.009 mol) in CHCl₃(25 mL) was added mCPBA (3.17 g, 0.01 mol). The reaction mixture wasthen stirred for 12 h at RT, quenched with a saturated Na₂CO₃ solution.The organic layer was separated, dried over Na₂SO₄ and concentrated invacuo to afford 2,6-dimethylpyridine 1-oxide (980 mg, 85%) as a solid.

(6-Methylpyridin-2-yl)methyl acetate

A solution of 2,6-dimethylpyridine 1-oxide (980 mg, 0.79 mmol) in aceticanhydride (5 mL) was refluxed for 1 h. The reaction mixture was thenconcentrated in vacuo to obtain the crude product. The crude materialwas purified via silica gel column chromatography using 20% ethylacetate in hexanes to afford (6-methylpyridin-2-yl)methyl acetate (1.0g) as a solid.

(6-Methylpyridin-2-yl)methanol hydrochloride

A solution of (6-methylpyridin-2-yl)methyl acetate (1.0 g) inconcentrated HCl (3 mL) was refluxed for 1 h. The reaction mixture wasthen concentrated in vacuo to obtain the crude product. The crudematerial was azeotroped with toluene, and the residue obtained wasfiltered and dried in vacuo to afford (6-methylpyridin-2-yl)methanolhydrochloride (811 mg) as a solid.

2-(Chloromethyl)-6-methylpyridine

A solution of (6-methylpyridin-2-yl)methanol hydrochloride (1.0 g, 0.008mol) in SOCl₂ (3 mL) was stirred at RT for 1 h. The reaction mixture wasthen concentrated in vacuo to obtain the crude product. The crudematerial was azeotroped with toluene and the resulting residue wasfiltered and dried in vacuo to afford 2-(chloromethyl)-6-methylpyridine(800 mg, 63%) as a light brown solid.

3-(4-methoxyphenyl)-4-(4-((6-methylpyridin-2-yl)methoxy)phenyl)furan-2(5H)-one(Example 1095)

To a solution of 4-(4-hydroxyphenyl)-3-(4-methoxyphenyl)furan-2(5H)-one(300 mg, 1.06 mmol) in DMF (10 mL) were added K₂CO₃ (294 mg, 2.12 mmol),2-(chloromethyl)-6-methylpyridine (225 mg, 1.59 mol) at RT. The reactionmixture was then heated at 80° C. for 16 h, quenched with ice and thenextracted with EtOAc (2×100 mL). The combined organic layers were washedwith water, dried over Na₂SO₄, and concentrated in vacuo to obtain thecrude product. The crude material was purified via silica gel columnchromatography to afford3-(4-methoxyphenyl)-4-(4-((6-methylpyridin-2-yl)methoxy)phenyl)furan-2(5H)-one(10 mg) as a solid. ¹H NMR (500 MHz, d₆-DMSO): δ 8.44 (d, J=7.2 Hz, 1H),7.79 (m, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.38-7.27(m, 3H), 7.16 (d, J=7.2 Hz, 2H), 6.99-6.92 (m, 2H), 5.41 (s, 2H), 5.33(s, 2H), 2.79 (s, 3H). MS: M⁺H: m/z=388.2.

Synthesis of4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 54)2-Bromo-1-(3-chloro-4-methoxyphenyl)ethanone

To a solution of 1-(3-chloro-4-methoxyphenyl)ethanone (1.0 g, 5.42 mmol)in MeOH (29.5 mL) was added a solution of bromine (0.33 mL, 6.50 mmol)in MeOH (10 mL) at RT. The reaction mixture was then stirred for 2 h,quenched with ice and extracted with DCM (2×20 mL). The combined organiclayers were washed with water, dried over Na₂SO₄, and concentrated invacuo to afford 2-bromo-1-(3-chloro-4-methoxyphenyl)ethanone (1.0 g,70%) as solid.

2-(3-chloro-4-methoxyphenyl)-2-oxoethyl2-(4-(quinolin-2-ylmethoxy)phenyl)acetate

To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (1.0 g,5.42 mmol) in acetonitrile (20 mL) were added Et₃N (5.54 mL, 43.4 mmol)and 2-bromo-1-(3-chloro-4-methoxyphenyl)ethanone (1.07 g, 3.65 mmol)under an inert atmosphere. The reaction mixture was then stirred at RTfor 1 h and concentrated in vacuo to obtain the crude product. The crudematerial was extracted with EtOAc (2×50 mL). The combined organic layerswere washed with water, dried over Na₂SO₄, and concentrated in vacuo toafford 2-(3-chloro-4-methoxyphenyl)-2-oxoethyl2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (750 mg, 29%) as a solid.

4-(3-Chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 54)

To a 0° C. solution of 2-(3-chloro-4-methoxyphenyl)-2-oxo-ethyl2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (750 mg, 1.58 mmol) in DMF (10mL) was added NaH (190 mg, 3.95 mmol). The reaction mixture was thenstirred at RT for 1 h, quenched with ice and extracted with EtOAc (2×50mL). The combined organic layers were washed with water, dried overNa₂SO₄, and concentrated in vacuo to obtain the crude product. The crudematerial was purified via silica gel column chromatography to afford4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (40 mg, 6%) as a solid. ¹H NMR (500 MHz, d₆-DMSO): δ8.42-8.38 (m, 1H), 8.16-8.05 (m, 2H), 7.72 (t, J=7.6 Hz, 1H), 7.49-7.39(m, 2H), 7.66 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.2 Hz, 1H), 7.42-7.36 (m,1H), 7.29-7.20 (m, 2H), 7.17-7.10 (m, 2H), 5.45 (s, 2H), 5.23 (s, 2H),3.85 (s, 3H). MS: M⁺H: m/z=458.1. HPLC: 93%, (Condition-H).

Synthesis of4-(3-fluoro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 53)4-(3-fluoro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 53)

Following the procedures for the preparation of4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one using 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanoneprovided the title compound. ¹H NMR (500 MHz, d₆-DMSO): δ 8.42-8.38 (m,1H), 8.16-8.05 (m, 2H), 7.72 (t, J=7.6 Hz, 1H), 7.49-7.39 (m, 2H), 7.66(d, J=8.2 Hz, 1H); 7.58 (t, J=7.2 Hz, 1H), 7.42-7.36 (m, 1H), 7.29-7.20(m, 2H), 7.17-7.10 (m, 2H), 5.45 (s, 2H), 5.23 (s, 2H), 3.85 (s, 3H).MS: M⁺H: m/z=442.2 and HPLC: 92%, (Condition-J).

Synthesis of 4-(4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 59)4-(4-Methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one(Example 59)

Following the procedure for the preparation of4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one using 2-bromo-1-(4-methoxyphenyl)ethanone provided thetitle compound. ¹H NMR (500 MHz, CDCl₃): δ 8.86-8.78 (m, 2H), 8.21 (d,J=7.8 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.68-7.64(m, 1H), 7.58-7.50 (m, 1H), 7.39 (d, J=7.2 Hz, 2H), 7.29-7.21 (m, 1H),7.02 (d, J=7.4 Hz, 2H), 6.92 (d, J=7.4 Hz, 2H), 5.41 (s, 2H), 5.05 (s,2H), 3.92 (s, 3H). MS: M⁺H: m/z=424.2; M⁺Na: m/z=446.1. HPLC: 90%,(Condition-C).

Synthesis of4-(4-methoxyphenyl)-1-methyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one(Example 125)4-(4-Methoxyphenyl)-1-methyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one(Example 125)

A stirred solution of4-(4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one(500 mg, 1.18 mmol) in 2N methanolic MeNH₂ (50 mL) was refluxed for 3 h.The reaction mixture was then concentrated in vacuo and the residue wasdissolved in 4N HCl in dioxane The reaction mixture was refluxed for 16h, then basified with aqueous NaHCO₃ solution and extracted with EtOAc(2×30 mL). The combined organic layers were washed with water, driedover Na₂SO₄, filtered, and concentrated in vacuo to obtain the crudeproduct. The crude material was purified via silica gel columnchromatography to afford4-(4-methoxyphenyl)-1-methyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one(150 mg, 29%) as a solid. ¹H NMR (500 MHz, d₆-DMSO): δ 8.43-8.39 (m,1H), 8.04-7.98 (m, 2H), 7.82-7.56 (m, 3H), 7.18-7.09 (m, 4H), 7.04 (d,J=7.2 Hz, 2H), 6.82 (d, J=7.2 Hz, 2H), 5.39 (s, 2H), 4.38 (s, 2H), 3.78(s, 3H), 2.99 (s, 3H). MS: M⁺H: m/z=437.1; M⁺Na: m/z=459.2; M⁺K:m/z=475.2 and HPLC: 87%, (Condition-B).

Synthesis of2-methoxy-5-(5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydrofuran-3-yl)benzonitrile(Example 55) 5-(2-bromoacetyl)-2-methoxybenzonitrile may be prepared bythe following scheme

2-Methoxy-5-(5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydrofuran-3-yl)benzonitrile(Example 55)

Following the procedure for the preparation of4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one-using 5-(2-bromoacetyl)-2-methoxybenzonitrile providedthe title compound. ¹H NMR (500 MHz, d₆-DMSO): δ 8.32-8.28 (m, 1H),8.06-7.95 (m, 2H), 7.81-7.76 (m, 2H), 7.62-7.56 (m, 1H), 7.49-7.39 (m,2H), 7.26-7.18 (m, 3H), 7.12-7.05 (m, 2H), 5.41 (s, 2H), 5.33 (s, 2H),3.89 (s, 3H). MS: M⁺H: m/z=449.0. HPLC: 91%., (Condition-H).

Synthesis of3-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one(Example 1099) Ethyl 2-(3-chloro-4-hydroxyphenyl)acetate

To a 0° C. solution of ethyl 2-(4-hydroxyphenyl)acetate (5.0 g, 0.02mol) in THF (100 mL) was added NCS (4.45 g, 0.03 mol). The reactionmixture was then stirred at RT for 16 h and then extracted with EtOAc(2×200 mL). The combined organic layers were washed with water, driedover Na₂SO₄, and concentrated in vacuo to afford ethyl2-(3-chloro-4-hydroxyphenyl)acetate (5 g, 84%) as a solid.

Ethyl 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetate

To a solution of compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (2.0g, 0.009 mol) in DMF (10 mL) was added K₂CO₃ (3.8 g, 0.02 mol) at RT.The reaction mixture was stirred for 10 minutes and then2-(chloromethyl) quinoline (1.2 g, 0.19 mol) was added. The reactionmixture was refluxed for 16 h, quenched with ice water and filtered. Theresidue that was obtained was extracted with DCM (2×100 mL). Thecombined organic layers were washed with water and brine, dried overNa₂SO₄, and concentrated in vacuo to afford ethyl2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetate (1.5 g, 45%) as asolid.

2-(3-Chloro-4-(quinolin-2-ylmethoxy)phenyl)acetic acid

To a solution of ethyl2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetate (1.0 g, 0.02 mol) in1:1 MeOH:THF (20 mL) was added LiOH.H₂O (1.76 g, 0.008 mol). Thereaction mixture was then stirred at RT for 16 h and then concentratedin vacuo to obtain the crude product. The crude material was dilutedwith water and adjusted to pH 4 using 1N HCl. The mixture was thenfiltered and the residue was dried in vacuo to afford2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetic acid (800 mg, 86%) asa solid.

3-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one(Example 1099)

To a stirred solution of2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetic acid (6.0 g, 0.01 mol)in acetonitrile (50 mL) were added TEA (2.58 mL, 0.02 mol) and2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (6.16 g, 0.02 mol) at RTunder an inert atmosphere. The reaction mixture was stirred for 30minutes, cooled to 0° C., and then DBU (5.5 mL, 0.03 mol) was added. Thereaction was stirred for an additional 15 minutes and then quenched withHCl (1 N) and extracted with DCM (2×300 mL). The combined organic layerswere washed with water, dried over Na₂SO₄, and concentrated in vacuo toobtain the crude product. The crude material was purified via silica gelcolumn chromatography to afford3-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one(500 mg) as a solid. ¹H NMR (500 MHz, d₆-DMSO): δ 8.64 (d, J=7.8 Hz,2H), 8.50-8.44 (m, 1H), 8.04-7.98 (m, 2H), 7.8 (t, J=7.2 Hz, 1H), 7.74(d, J=7.6 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.50 (s, 1H), 7.38-7.32 (m,3H), 7.26-7.22 (m, 1H), 5.55 (s, 2H), 5.38 (s, 2H). MS: M⁺H: m/z=429.1.HPLC: 90%, (Condition-I).

Tables

In the following tables of examples, if a specific example contains asingle value in the column “R_(1a) and R_(1b)”, then both R_(1a) andR_(1b) (if present) are taken to be this value. If this column containsmultiple values separated by a comma, the first value is taken to beR_(1a) and the second to be R_(1b). In the following tables, if aspecific example contains multiple instances of R₂, they will beseparated by commas in the table (e.g. Me, Me or Et, Me). If the R₂column contains a value “-group-” e.g. “-cyclopropyl-”, then both R₂values are taken together to be a spiro ring.

In a further aspect the compounds of the disclosure are embodied in withdistinct examples listed in the table below taken from Formula (I):

Ex. # HET X Y Z R_(1a), R_(1b) R₂ R₃ R₄ R₇ 1 A1 4-pyridinyl OCH₂2-quinoline — — H H — 2 A1 4-pyridinyl OCH₂ 2-benzimidazole — — H H — 3A1 4-pyridinyl OCH₂ 2-tetrahydroisoquinoline — — H H — 4 A1 4-pyridinylOCH₂ 2-pyridinyl — — H H — 5 A1 4-pyridinyl OCH₂ 2-benzoxazole — — H H —6 A1 4-pyridinyl OCH₂ 2-benzthiazole — — H H — 7 A1 4-pyridinyl OCH₂2-quinoxaline — — H H — 8 A1 4-pyridinyl OCH₂ 2-naphthyridine — — H H —9 A1 4-pyridinyl OCH₂ 2-quinazoline — — H H — 10 A1 3-pyridinyl OCH₂2-quinoline — — H H — 11 A1 3,4-diOMe—Ph OCH₂ 2-quinoline — — H H — 12A1 3-Me-4-pyridinyl OCH₂ 2-quinoline — — H H — 13 A1 3-OMe-4-pyridinylOCH₂ 2-quinoline — — H H — 14 A1 4-OMe-phenyl OCH₂ 2-quinoline — — H H —15 A1 4-pyridinyl CH₂O 2-quinoline — — H H — 16 A2 4-pyridinyl OCH₂2-quinoline — — H H H 17 A2 4-pyridinyl OCH₂ 2-benzimidazole — — H H Me18 A2 4-pyridinyl OCH₂ 2-tetrahydroisoquinoline — — H H Me 19 A24-pyridinyl OCH₂ 2-pyridinyl — — H H Me 20 A2 4-pyridinyl OCH₂2-benzoxazole — — H H Me 21 A2 4-pyridinyl OCH₂ 2-benzthiazole — — H HMe 22 A2 4-pyridinyl OCH₂ 2-quinoxaline — — H H Me 23 A2 4-pyridinylOCH₂ 2-naphthyridine — — H H Me 24 A2 4-pyridinyl OCH₂ 2-quinazoline — —H H Me 25 A2 3-pyridinyl OCH₂ 2-quinoline — — H H H 26 A2 3,4-diOMe—PhOCH₂ 2-quinoline — — H H H 27 A2 3-Me-4-pyridinyl OCH₂ 2-quinoline — — HH H 28 A2 3-OMe-4-pyridinyl OCH₂ 2-quinoline — — H H H 29 A24-OMe-phenyl OCH₂ 2-quinoline — — H H H 30 A2 4-pyridinyl OCH₂2-quinoline — — H H Me 31 A2 4-pyridinyl CH₂O 2-quinoline — — H H H 32A2 4-pyridinyl CH₂O 2-quinoline — — H H Me 33 A3 4-pyridinyl OCH₂2-quinoline — — — — H 34 A3 4-pyridinyl CH₂O 2-quinoline — — — — H 35 A64-pyridinyl OCH₂ 2-quinoline H, — — — — H 36 A6 4-pyridinyl CH₂O2-quinoline H, — — — — H 37 A7 4-pyridinyl OCH₂ 2-quinoline — — H H — 38A7 4-pyridinyl OCH₂ 2-tetrahydroisoquinoline — — H H — 39 A7 4-pyridinylOCH₂ 2-pyridinyl — — H H — 40 A7 4-pyridinyl OCH₂ 2-benzoxazole — — H H— 41 A7 4-pyridinyl OCH₂ 2-benzthiazole — — H H — 42 A7 4-pyridinyl OCH₂2-quinoxaline — — H H — 43 A7 4-pyridinyl OCH₂ 2-naphthyridine — — H H —44 A7 4-pyridinyl OCH₂ 2-quinazoline — — H H — 45 A7 4-pyridinyl CH₂O2-quinoline — — H H — 46 A7 4-pyramidinyl OCH₂ 2-quinoline — — H H — 47A7 4-pyrazolyl OCH₂ 2-quinoline — — H H — 48 A7 5-pyridin-2(1H)-onylOCH₂ 2-quinoline — — H H — 49 A7 4-pyridin-2(1H)-onyl OCH₂ 2-quinoline —— H H — 50 A7 4-pyridazinyl OCH₂ 2-quinoline — — H H — 51 A73-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H — 52 A74-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H — 53 A7 3-F,4-OMephenyl OCH₂ 2-quinoline — — H H — 54 A7 3-Cl,4-OMe phenyl OCH₂2-quinoline — — H H — 55 A7 3-CN,4-OMe phenyl OCH₂ 2-quinoline — — H H —56 A7 3-OMe,4-F phenyl OCH₂ 2-quinoline — — H H — 57 A7 3-OMe,4-Clphenyl OCH₂ 2-quinoline — — H H — 58 A7 3-OMe,4-CN phenyl OCH₂2-quinoline — — H H — 59 A7

OCH₂ 2-quinoline — — H H — 60 A7

OCH₂ 2-quinoline — — H H — 61 A7

OCH₂ 2-quinoline — — H H — 62 A7

OCH₂ 2-quinoline — — H H — 63 A7

OCH₂ 2-quinoline — — H H — 64 A7

OCH₂ 2-quinoline — — H H — 65 A7

OCH₂ 2-quinoline — — H H — 66 A7

OCH₂ 2-quinoline — — H H — 67 A7

OCH₂ 2-quinoline — — H H — 68 A7

OCH₂ 2-quinoline — — H H — 69 A7

OCH₂ 2-quinoline — — H H — 70 A7

OCH₂ 2-quinoline — — H H — 71 A7

OCH₂ 2-quinoline — — H H — 72 A7

OCH₂ 2-quinoline — — H H — 73 A7

OCH₂ 2-quinoline — — H H — 74 A7

OCH₂ 2-quinoline — — H H — 75 A7

OCH₂ 2-quinoline — — H H — 76 A7

OCH₂ 2-quinoline — — H H — 77 A7

OCH₂ 2-quinoline — — H H — 78 A7

OCH₂ 2-quinoline — — H H — 79 A7

OCH₂ 2-quinoline — — H H — 80 A7

OCH₂ 2-quinoline — — H H — 81 A7

OCH₂ 2-quinoline — — H H — 82 A7

OCH₂ 2-quinoline — — H H — 83 A7

OCH₂ 2-quinoline — — H H — 84 A7

OCH₂ 2-quinoline — — H H — 85 A8 4-pyridinyl OCH₂ 2-quinoline — — H H H86 A8 4-pyridinyl OCH₂ 2-benzimidazole — — H H Me 87 A8 4-pyridinyl OCH₂2-tetrahydroisoquinoline — — H H Me 88 A8 4-pyridinyl OCH₂ 2-pyridinyl —— H H Me 89 A8 4-pyridinyl OCH₂ 2-benzoxazole — — H H Me 90 A84-pyridinyl OCH₂ 2-benzthiazole — — H H Me 91 A8 4-pyridinyl OCH₂2-quinoxaline — — H H Me 92 A8 4-pyridinyl OCH₂ 2-naphthyridine — — H HMe 93 A8 4-pyridinyl OCH₂ 2-quinazoline — — H H Me 94 A8 4-pyridinylOCH₂ 2-quinoline — — H H Me 95 A8 4-pyridinyl CH₂O 2-quinoline — — H H H96 A8 4-pyridinyl CH₂O 2-quinoline — — H H Me 97 A8 4-pyridinyl OCH₂2-quinoline — — H H cyclopropyl 98 A8 4-pyridinyl OCH₂ 2-quinoline — — HH —CH₂CF₃ 99 A8

OCH₂ 2-quinoline — — H H H 100 A8

OCH₂ 2-quinoline — — H H H 101 A8

OCH₂ 2-quinoline — — H H H 102 A8

OCH₂ 2-quinoline — — H H H 103 A8

OCH₂ 2-quinoline — — H H H 104 A8

OCH₂ 2-quinoline — — H H H 105 A8

OCH₂ 2-quinoline — — H H H 106 A8

OCH₂ 2-quinoline — — H H H 107 A8

OCH₂ 2-quinoline — — H H H 108 A8

OCH₂ 2-quinoline — — H H H 109 A8

OCH₂ 2-quinoline — — H H H 110 A8

OCH₂ 2-quinoline — — H H H 111 A8

OCH₂ 2-quinoline — — H H H 112 A8

OCH₂ 2-quinoline — — H H H 113 A8

OCH₂ 2-quinoline — — H H H 114 A8

OCH₂ 2-quinoline — — H H H 115 A8

OCH₂ 2-quinoline — — H H H 116 A8

OCH₂ 2-quinoline — — H H H 117 A8

OCH₂ 2-quinoline — — H H H 118 A8

OCH₂ 2-quinoline — — H H H 119 A8

OCH₂ 2-quinoline — — H H H 120 A8

OCH₂ 2-quinoline — H H H 121 A8

OCH₂ 2-quinoline — — H H H 122 A8

OCH₂ 2-quinoline — — H H H 123 A8

OCH₂ 2-quinoline — — H H H 124 A8

OCH₂ 2-quinoline — — H H H 125 A8

OCH₂ 2-quinoline — — H H Me 126 A8

OCH₂ 2-quinoline — — H H Me 127 A8

OCH₂ 2-quinoline — — H H Me 128 A8

OCH₂ 2-quinoline — — H H Me 129 A8

OCH₂ 2-quinoline — — H H Me 130 A8

OCH₂ 2-quinoline — — H H Me 131 A8

OCH₂ 2-quinoline — — H H Me 132 A8

OCH₂ 2-quinoline — — H H Me 133 A8

OCH₂ 2-quinoline — — H H Me 134 A8

OCH₂ 2-quinoline — — H H Me 135 A8

OCH₂ 2-quinoline — — H H Me 136 A8

OCH₂ 2-quinoline — — H H Me 137 A8

OCH₂ 2-quinoline — — H H Me 138 A8

OCH₂ 2-quinoline — — H H Me 139 A8

OCH₂ 2-quinoline — — H H Me 140 A8

OCH₂ 2-quinoline — — H H Me 141 A8

OCH₂ 2-quinoline — — H H Me 142 A8

OCH₂ 2-quinoline — — H H Me 143 A8

OCH₂ 2-quinoline — — H H Me 144 A8

OCH₂ 2-quinoline — — H H Me 145 A8

OCH₂ 2-quinoline — — H H Me 146 A8

OCH₂ 2-quinoline — — H H Me 147 A8

OCH₂ 2-quinoline — — H H Me 148 A8

OCH₂ 2-quinoline — — H H Me 149 A8

OCH₂ 2-quinoline — — H H Me 150 A8

OCH₂ 2-quinoline — — H H Me 151 A10 4-pyridinyl OCH₂ 2-quinoline H, — —— — — 153 A11 4-pyridinyl OCH₂ 2-quinoline H, — — — — — 154 A114-pyridinyl CH₂O 2-quinoline H, — — — — — 155 A12 4-pyridinyl OCH₂2-quinoline H, — — — — — 156 A12 4-pyridinyl CH₂O 2-quinoline H, — — — —— 157 A13 4-pyridinyl OCH₂ 2-quinoline H, H — — — — 158 A13 4-pyridinylCH₂O 2-quinoline H, H — — — — 159 A14 4-pyridinyl OCH₂ 2-quinoline H, H— — — — 160 A14 4-pyridinyl CH₂O 2-quinoline H, H — — — — 161 A144-pyridinyl CH₂O 2-quinoline H, Me — — — — 162 A15 4-pyridinyl OCH₂2-quinoline H, — — — — — 163 A15 4-pyridinyl CH₂O 2-quinoline H, — — — —— 164 A25 4-pyridinyl OCH₂ 2-quinoline — H — — — 165 A29

OCH₂ 2-quinoline — H, H — — — 166 A29

OCH₂ 2-quinoline — H, H — — — 167 A29

OCH₂ 2-quinoline — H, H — — — 168 A29

OCH₂ 2-quinoline — H, H — — — 169 A29

OCH₂ 2-quinoline — H, H — — — 170 A29

OCH₂ 2-quinoline — H, H — — — 171 A29

OCH₂ 2-quinoline — H, H — — — 172 A29

OCH₂ 2-quinoline — H, H — — — 173 A29

OCH₂ 2-quinoline — H, H — — — 174 A29

OCH₂ 2-quinoline — H, H — — — 175 A29

OCH₂ 2-quinoline — H, H — — — 176 A29

OCH₂ 2-quinoline — H, H — — — 177 A29

OCH₂ 2-quinoline — H, H — — — 178 A29

OCH₂ 2-quinoline — H, H — — — 179 A29

OCH₂ 2-quinoline — H, H — — — 180 A29

OCH₂ 2-quinoline — H, H — — — 181 A29

OCH₂ 2-quinoline — H, H — — — 182 A29

OCH₂ 2-quinoline — H, H — — — 183 A29

OCH₂ 2-quinoline — H, H — — — 184 A29

OCH₂ 2-quinoline — H, H — — — 185 A29

OCH₂ 2-quinoline — H, H — — — 186 A29

OCH₂ 2-quinoline — H, H — — — 187 A29

OCH₂ 2-quinoline — H, H — — — 188 A29

OCH₂ 2-quinoline — H, H — — — 189 A29

OCH₂ 2-quinoline — H, H — — — 190 A29

OCH₂ 2-quinoline — H, H — — — 191 A29

OCH₂ 2-quinoline — H, H — — — 192 A29

OCH₂ 2-quinoline — H, H — — — 193 A29

OCH₂ 2-quinoline — H, H — — — 194 A29

OCH₂ 2-quinoline — H, H — — — 195 A29

OCH₂ 2-quinoline — H, H — — — 196 A29

OCH₂ 2-quinoline — H, H — — — 197 A29

OCH₂ 2-quinoline — H, H — — — 198 A29

OCH₂ 2-quinoline — H, H — — — 199 A29

OCH₂ 2-quinoline — H, H — — — 200 A29

OCH₂ 2-quinoline — H, H — — — 201 A29

OCH₂ 2-quinoline — H, H — — — 202 A29

OCH₂ 2-quinoline — H, H — — — 203 A29

OCH₂ 2-quinoline — H, H — — — 204 A29

OCH₂ 2-quinoline — H, H — — — 205 A29

OCH₂ 2-quinoline — H, H — — — 206 A29

OCH₂ 2-quinoline — H, H — — — 207 A29

OCH₂ 2-quinoline — H, H — — — 208 A29

OCH₂ 2-quinoline — H, H — — — 209 A29

OCH₂ 2-quinoline — H, H — — — 210 A29

OCH₂ 2-quinoline — H, H — — — 211 A29

OCH₂ 2-quinoline — H, H — — — 212 A29

OCH₂

— H, H — — — 213 A29

OCH₂

— H, H — — — 214 A29

OCH₂

— H, H — — — 215 A29

OCH₂

— H, H — — — 216 A29

OCH₂

— H, H — — — 217 A29

OCH₂

— H, H — — — 218 A29

OCH₂

— H, H — — — 219 A29

OCH₂

— H, H — — — 220 A29

OCH₂

— H, H — — — 221 A29

OCH₂

— H, H — — — 222 A29

OCH₂

— H, H — — — 223 A29

OCH₂

— H, H — — — 224 A29

OCH₂

— H, H — — — 225 A29

OCH₂

— H, H — — — 226 A29

OCH₂

— H, H — — — 227 A29

OCH₂

— H, H — — — 228 A29

OCH₂

— H, H — — — 229 A29

OCH₂

— H, H — — — 230 A29

OCH₂

— H, H — — — 231 A29

OCH₂

— H, H — — — 232 A29

OCH₂

— H, H — — — 233 A29

OCH₂

— H, H — — — 234 A29

OCH₂

— H, H — — — 235 A29

OCH₂

— H, H — — — 236 A29

OCH₂

— H, H — — — 237 A29

OCH₂

— H, H — — — 238 A29

OCH₂

— H, H — — — 239 A29

OCH₂

— H, H — — — 240 A29

OCH₂

— H, H — — — 241 A29

OCH₂

— H, H — — — 242 A29

OCH₂

— H, H — — — 243 A29

OCH₂

— H, H — — — 244 A29

OCH₂

— H, H — — — 245 A29

OCH₂

— H, H — — — 246 A29

OCH₂

— H, H — — — 247 A29

OCH₂

— H, H — — — 248 A29

OCH₂

— H, H — — — 249 A29

OCH₂

— H, H — — — 250 A29

OCH₂

— H, H — — — 251 A29

OCH₂

— H, H — — — 252 A29

OCH₂

— H, H — — — 253 A29

OCH₂

— H, H — — — 254 A29

OCH₂

— H, H — — — 255 A29

OCH₂

— H, H — — — 256 A29

OCH₂

— H, H — — — 257 A29

OCH₂

— H, H — — — 258 A30

OCH₂ 2-quinoline — H, H — — H 259 A30

OCH₂ 2-quinoline — H, H — — H 260 A30

OCH₂ 2-quinoline — H, H — — H 261 A30

OCH₂ 2-quinoline — H, H — — H 262 A30

OCH₂ 2-quinoline — H, H — — H 263 A30

OCH₂ 2-quinoline — H, H — — H 264 A30

OCH₂ 2-quinoline — H, H — — H 265 A30

OCH₂ 2-quinoline — H, H — — H 266 A30

OCH₂ 2-quinoline — H, H — — H 267 A30

OCH₂ 2-quinoline — H, H — — H 268 A30

OCH₂ 2-quinoline — H, H — — H 269 A30

OCH₂ 2-quinoline — H, H — — H 270 A30

OCH₂ 2-quinoline — H, H — — H 271 A30

OCH₂ 2-quinoline — H, H — — H 272 A30

OCH₂ 2-quinoline — H, H — — H 273 A30

OCH₂ 2-quinoline — H, H — — H 274 A30

OCH₂ 2-quinoline — H, H — — H 275 A30

OCH₂ 2-quinoline — H, H — — H 276 A30

OCH₂ 2-quinoline — H, H — — H 277 A30

OCH₂ 2-quinoline — H, H — — H 278 A30

OCH₂ 2-quinoline — H, H — — H 279 A30

OCH₂ 2-quinoline — H, H — — H 280 A30

OCH₂ 2-quinoline — H, H — — H 281 A30

OCH₂ 2-quinoline — H, H — — H 282 A30

OCH₂ 2-quinoline — H, H — — Me 283 A30

OCH₂ 2-quinoline — H, H — — Me 284 A30

OCH₂ 2-quinoline — H, H — — Me 285 A30

OCH₂ 2-quinoline — H, H — — Me 286 A30

OCH₂ 2-quinoline — H, H — — Me 287 A30

OCH₂ 2-quinoline — H, H — — Me 288 A30

OCH₂ 2-quinoline — H, H — — Me 289 A30

OCH₂ 2-quinoline — H, H — — Me 290 A30

OCH₂ 2-quinoline — H, H — — Me 291 A30

OCH₂ 2-quinoline — H, H — — Me 292 A30

OCH₂ 2-quinoline — H, H — — Me 293 A30

OCH₂ 2-quinoline — H, H — — Me 294 A30

OCH₂ 2-quinoline — H, H — — Me 295 A30

OCH₂ 2-quinoline — H, H — — Me 296 A30

OCH₂ 2-quinoline — H, H — — Me 297 A30

OCH₂ 2-quinoline — H, H — — Me 298 A30

OCH₂ 2-quinoline — H, H — — Me 299 A30

OCH₂ 2-quinoline — H, H — — Me 300 A30

OCH₂ 2-quinoline — H, H — — Me 301 A30

OCH₂ 2-quinoline — H, H — — Me 302 A30

OCH₂ 2-quinoline — H, H — — Me 303 A30

OCH₂ 2-quinoline — H, H — — Me 304 A30

OCH₂ 2-quinoline — H, H — — Me 305 A30

OCH₂ 2-quinoline — H, H — — Me 306 A31 4-pyridinyl OCH₂ 2-quinoline — H,H — — — 307 A31

OCH₂ 2-quinoline — H, H — — — 308 A31

OCH₂ 2-quinoline — H, H — — — 309 A31

OCH₂ 2-quinoline — H, H — — — 310 A31

OCH₂ 2-quinoline — H, H — — — 311 A31

OCH₂ 2-quinoline — H, H — — — 312 A31

OCH₂ 2-quinoline — H, H — — — 313 A31

OCH₂ 2-quinoline — H, H — — — 314 A31

OCH₂ 2-quinoline — H, H — — — 315 A31

OCH₂ 2-quinoline — H, H — — — 316 A31

OCH₂ 2-quinoline — H, H — — — 317 A31

OCH₂ 2-quinoline — H, H — — — 318 A31

OCH₂ 2-quinoline — H, H — — — 319 A31

OCH₂ 2-quinoline — H, H — — — 320 A31

OCH₂ 2-quinoline — H, H — — — 321 A31

OCH₂ 2-quinoline — H, H — — — 322 A31

OCH₂ 2-quinoline — H, H — — — 323 A31

OCH₂ 2-quinoline — H, H — — — 324 A31

OCH₂ 2-quinoline — H, H — — — 325 A31

OCH₂ 2-quinoline — H, H — — — 326 A31

OCH₂ 2-quinoline — H, H — — — 327 A31

OCH₂ 2-quinoline — H, H — — — 328 A31

OCH₂ 2-quinoline — H, H — — — 329 A31

OCH₂ 2-quinoline — H, H — — — 330 A31

OCH₂ 2-quinoline — H, H — — — 331 A31

OCH₂ 2-quinoline — H, H — — — 332 A31

OCH₂ 2-quinoline — H, H — — — 333 A31

OCH₂ 2-quinoline — H, H — — — 334 A31

OCH₂ 2-quinoline — H, H — — — 335 A31

OCH₂ 2-quinoline — H, H — — — 336 A31

OCH₂ 2-quinoline — H, H — — — 337 A31

OCH₂ 2-quinoline — H, H — — — 338 A31

OCH₂ 2-quinoline — H, H — — — 339 A31

OCH₂ 2-quinoline — H, H — — — 340 A31

OCH₂ 2-quinoline — H, H — — — 341 A31

OCH₂ 2-quinoline — H, H — — — 342 A31

OCH₂ 2-quinoline — H, H — — — 343 A31

OCH₂ 2-quinoline — H, H — — — 344 A31

OCH₂ 2-quinoline — H, H — — — 345 A31

OCH₂ 2-quinoline — H, H — — — 346 A31

OCH₂ 2-quinoline — H, H — — — 347 A31

OCH₂ 2-quinoline — H, H — — — 348 A31

OCH₂ 2-quinoline — H, H — — — 349 A31

OCH₂ 2-quinoline — H, H — — — 350 A31

OCH₂ 2-quinoline — H, H — — — 351 A31

OCH₂ 2-quinoline — H, H — — — 352 A31

OCH₂ 2-quinoline — H, H — — — 353 A31

OCH₂ 2-quinoline — H, H — — — 354 A31

OCH₂

— H, H — — — 355 A31

OCH₂

— H, H — — — 356 A31

OCH₂

— H, H — — — 357 A31

OCH₂

— H, H — — — 358 A31

OCH₂

— H, H — — — 359 A31

OCH₂

— H, H — — — 360 A31

OCH₂

— H, H — — — 361 A31

OCH₂

— H, H — — — 362 A31

OCH₂

— H, H — — — 363 A31

OCH₂

— H, H — — — 364 A31

OCH₂

— H, H — — — 365 A31

OCH₂

— H, H — — — 366 A31

OCH₂

— H, H — — — 367 A31

OCH₂

— H, H — — — 368 A31

OCH₂

— H, H — — — 369 A31

OCH₂

— H, H — — — 370 A31

OCH₂

— H, H — — — 371 A31

OCH₂

— H, H — — — 372 A31

OCH₂

— H, H — — — 373 A31

OCH₂

— H, H — — — 374 A31

OCH₂

— H, H — — — 375 A31

OCH₂

— H, H — — — 376 A31

OCH₂

— H, H — — — 377 A31

OCH₂

— H, H — — — 378 A31

OCH₂

— H, H — — — 379 A31

OCH₂

— H, H — — — 380 A31

OCH₂

— H, H — — 381 A31

OCH₂

— H, H — — — 382 A31

OCH₂

— H, H — — — 383 A31

OCH₂

— H, H — — — 384 A31

OCH₂

— H, H — — — 385 A31

OCH₂

— H, H — — — 386 A31

OCH₂

— H, H — — — 387 A31

OCH₂

— H, H — — — 388 A31

OCH₂

— H, H — — — 389 A31

OCH₂

— H, H — — — 390 A31

OCH₂

— H, H — — — 391 A31

OCH₂

— H, H — — — 392 A31

OCH₂

— H, H — — — 393 A31

OCH₂

— H, H — — — 394 A31

OCH₂

— H, H — — — 395 A31

OCH₂

— H, H — — — 396 A31

OCH₂

— H, H — — — 397 A31

OCH₂

— H, H — — — 398 A31

OCH₂

— H, H — — — 399 A31

OCH₂

— H, H — — — 400 A31

OCH₂

— H, H — — — 401 A31

OCH₂

— H, H — — — 402 A31

OCH₂

— H, H — — — 403 A31

OCH₂

— H, H — — — 404 A31

OCH₂

— H, H — — — 405 A31

OCH₂

— H, H — — — 406 A31

OCH₂

— H, H — — — 407 A31

OCH₂

— H, H — — — 408 A31

OCH₂

— H, H — — — 409 A31

OCH₂

— H, H — — — 410 A31

OCH₂

— H, H — — — 411 A31

OCH₂

— H, H — — — 412 A31

OCH₂

— H, H — — — 413 A31

OCH₂

— H, H — — — 414 A31

OCH₂

— H, H — — — 415 A31

OCH₂

— H, H — — — 416 A31

OCH₂

— H, H — — — 417 A31

OCH₂

— H, H — — — 418 A31

OCH₂

— H, H — — — 419 A31

OCH₂

— H, H — — — 420 A31

OCH₂

— H, H — — — 421 A31

OCH₂

— H, H — — — 422 A31

OCH₂

— H, H — — — 1085 A7

OCH₂ 2-quinoline — — H H — 1086 A7

OCH₂ 2-quinoline — — H H — 1087 A7

OCH₂ 2-quinoline — — H H — 1088 A8

OCH₂ 2-quinoline — — H H H 1089 A8

OCH₂ 2-quinoline — — H H H 1090 A8

OCH₂ 2-quinoline — — H H H 1091 A8

OCH₂ 2-quinoline — — H H Me 1092 A8

OCH₂ 2-quinoline — — H H Me 1093 A8

OCH₂ 2-quinoline — — H H Me 1094 A16

OCH₂ 2-quinoline H — — — — 1095 A1

OCH₂

— — H H — 1096 A18

OCH₂ 2-quinoline H, H — — — — 1097 A18

OCH₂ 2-quinoline Me, H — — — — 1098 A7

OCH₂ 2-quinoline — — H H — 1100 A13 4-pyridinyl OCH₂ 2-quinoline Me, H —— — — 1101 A14 4-pyridinyl OCH₂ 2-quinoline Me, H — — — —

In a further aspect the compounds of the disclosure are embodied in withdistinct examples listed in the table below taken from Formula (II):

Ex. # HET W X Y Z R_(1a) , R_(1b) R₂ R₃ R₄ R₇ 423 A1  Cl 4-pyridinylOCH₂ 2-quinoline — — H H — 424 A1  Cl 4-OMe-phenyl OCH₂ 2-quinoline — —H H — 425 A1  Cl 4-pyrazolyl OCH₂ 2-quinoline — — H H — 426 A1  Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H — 427 A1  Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H — 428 A1  Cl

OCH₂ 2-quinoline — — H H — 429 A1  Cl

OCH₂ 2-quinoline — — H H — 430 A1  Cl

OCH₂ 2-quinoline — — H H — 431 A1  Cl

OCH₂ 2-quinoline — — H H — 432 A1  Cl

OCH₂ 2-quinoline — — H H — 433 A1  Cl

OCH₂ 2-quinoline — — H H — 434 A1  Cl

OCH₂ 2-quinoline — — H H — 435 A1  Cl

OCH₂ 2-quinoline — — H H — 436 A2  Cl 4-pyridinyl OCH₂ 2-quinoline — — HH H 437 A2  Cl 4-pyridinyl OCH₂ 2-quinoline — — H H Me 439 A2  Cl4-OMe-phenyl OCH₂ 2-quinoline — — H H H 440 A2  Cl 4-OMe-phenyl OCH₂2-quinoline — — H H Me 442 A2  Cl 4-pyrazolyl OCH₂ 2-quinoline — — H H H443 A2  Cl 4-pyrazolyl OCH₂ 2-quinoline — — H H Me 445 A2  Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H H 446 A2  Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H Me 448 A2  Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H H 449 A2  Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H Me 450 A2  Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — Me Me H 451 A2  Cl

OCH₂ 2-quinoline — — H H H 452 A2  Cl

OCH₂ 2-quinoline — — H H Me 454 A2  Cl

OCH₂ 2-quinoline — — H H H 455 A2  Cl

OCH₂ 2-quinoline — — H H Me 457 A2  Cl

OCH₂ 2-quinoline — — H H H 458 A2  Cl

OCH₂ 2-quinoline — — H H Me 460 A2  Cl

OCH₂ 2-quinoline — — H H H 461 A2  Cl

OCH₂ 2-quinoline — — H H Me 463 A2  Cl

OCH₂ 2-quinoline — — H H H 464 A2  Cl

OCH₂ 2-quinoline — — H H Me 466 A2  Cl

OCH₂ 2-quinoline — — H H H 467 A2  Cl

OCH₂ 2-quinoline — — H H Me 469 A2  Cl

OCH₂ 2-quinoline — — H H H 470 A2  Cl

OCH₂ 2-quinoline — — H H Me 472 A2  Cl

OCH₂ 2-quinoline — — H H H 473 A2  Cl

OCH₂ 2-quinoline — — H H Me 475 A6  Cl 4-pyridinyl OCH₂ 2-quinoline H, —— — — H 476 A6  Cl 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — H 477 A6  Cl4-pyrazolyl OCH₂ 2-quinoline H, — — — — H 478 A6  Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — H 479 A6  Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — H 480 A6  Cl

OCH₂ 2-quinoline H, — — — — H 481 A6  Cl

OCH₂ 2-quinoline H, — — — — H 482 A6  Cl

OCH₂ 2-quinoline H, — — — — H 483 A6  Cl

OCH₂ 2-quinoline H, — — — — H 484 A6  Cl

OCH₂ 2-quinoline H, — — — — H 485 A6  Cl

OCH₂ 2-quinoline H, — — — — H 486 A6  Cl

OCH₂ 2-quinoline H, — — — — H 487 A6  Cl

OCH₂ 2-quinoline H, — — — — H 488 A11 Cl 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 489 A11 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 490 A11Cl 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 491 A11 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 492 A11 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 493 A11 Cl

OCH₂ 2-quinoline H, — — — — — 494 A11 Cl

OCH₂ 2-quinoline H, — — — — — 495 A11 Cl

OCH₂ 2-quinoline H, — — — — — 496 A11 Cl

OCH₂ 2-quinoline H, — — — — — 497 A11 Cl

OCH₂ 2-quinoline H, — — — — — 498 A11 Cl

OCH₂ 2-quinoline H, — — — — — 499 A11 Cl

OCH₂ 2-quinoline H, — — — — — 500 A11 Cl

OCH₂ 2-quinoline H, — — — — — 501 A12 Cl 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 502 A12 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 503 A12Cl 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 504 A12 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 505 A12 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 506 A12 Cl

OCH₂ 2-quinoline H, — — — — — 507 A12 Cl

OCH₂ 2-quinoline H, — — — — — 508 A12 Cl

OCH₂ 2-quinoline H, — — — — — 509 A12 Cl

OCH₂ 2-quinoline H, — — — — — 510 A12 Cl

OCH₂ 2-quinoline H, — — — — — 511 A12 Cl

OCH₂ 2-quinoline H, — — — — — 512 A12 Cl

OCH₂ 2-quinoline H, — — — — — 513 A12 Cl

OCH₂ 2-quinoline H, — — — — — 514 A13 Cl 4-pyridinyl OCH₂ 2-quinoline H,H — — — — 515 A13 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 516 A13Cl 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 517 A13 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 518 A13 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 519 A13 Cl

OCH₂ 2-quinoline H, H — — — — 520 A13 Cl

OCH₂ 2-quinoline H, H — — — — 521 A13 Cl

OCH₂ 2-quinoline H, H — — — — 522 A13 Cl

OCH₂ 2-quinoline H, H — — — — 523 A13 Cl

OCH₂ 2-quinoline H, H — — — — 524 A13 Cl

OCH₂ 2-quinoline H, H — — — — 525 A13 Cl

OCH₂ 2-quinoline H, H — — — — 526 A13 Cl

OCH₂ 2-quinoline H, H — — — — 527 A14 Cl 4-pyridinyl OCH₂ 2-quinoline H,H — — — — 528 A14 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 529 A14Cl 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 530 A14 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 531 A14 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 532 A14 Cl

OCH₂ 2-quinoline H, H — — — — 533 A14 Cl

OCH₂ 2-quinoline H, H — — — — 534 A14 Cl

OCH₂ 2-quinoline H, H — — — — 535 A14 Cl

OCH₂ 2-quinoline H, H — — — — 536 A14 Cl

OCH₂ 2-quinoline H, H — — — — 537 A14 Cl

OCH₂ 2-quinoline H, H — — — — 538 A14 Cl

OCH₂ 2-quinoline H, H — — — — 539 A14 Cl

OCH₂ 2-quinoline H, H — — — — 540 A15 Cl 4-pyridinyl OCH₂ 2-quinoline H,H — — — — 541 A15 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 542 A15Cl 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 543 A15 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 544 A15 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 545 A15 Cl

OCH₂ 2-quinoline H, H — — — — 546 A15 Cl

OCH₂ 2-quinoline H, H — — — — 547 A15 Cl

OCH₂ 2-quinoline H, H — — — — 548 A15 Cl

OCH₂ 2-quinoline H, H — — — — 549 A15 Cl

OCH₂ 2-quinoline H, H — — — — 550 A15 Cl

OCH₂ 2-quinoline H, H — — — — 551 A15 Cl

OCH₂ 2-quinoline H, H — — — — 552 A15 Cl

OCH₂ 2-quinoline H, H — — — — 553 A19 Cl 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 554 A19 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 555 A19Cl 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 556 A19 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 557 A19 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 558 A19 Cl

OCH₂ 2-quinoline H, — — — — — 559 A19 Cl

OCH₂ 2-quinoline H, — — — — — 560 A19 Cl

OCH₂ 2-quinoline H, — — — — — 561 A19 Cl

OCH₂ 2-quinoline H, — — — — — 562 A19 Cl

OCH₂ 2-quinoline H, — — — — — 563 A19 Cl

OCH₂ 2-quinoline H, — — — — — 564 A19 Cl

OCH₂ 2-quinoline H, — — — — — 565 A19 Cl

OCH₂ 2-quinoline H, — — — — — 566 A20 Cl 4-pyridinyl OCH₂ 2-quinoline H,H — — — — 567 A20 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 568 A20Cl 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 569 A20 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 570 A20 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 571 A20 Cl

OCH₂ 2-quinoline H, H — — — — 572 A20 Cl

OCH₂ 2-quinoline H, H — — — — 573 A20 Cl

OCH₂ 2-quinoline H, H — — — — 574 A20 Cl

OCH₂ 2-quinoline H, H — — — — 575 A20 Cl

OCH₂ 2-quinoline H, H — — — — 576 A20 Cl

OCH₂ 2-quinoline H, H — — — — 577 A20 Cl

OCH₂ 2-quinoline H, H — — — — 578 A20 Cl

OCH₂ 2-quinoline H, H — — — — 579 A32 Cl 4-pyridinyl OCH₂ 2-quinoline —H, H — — H 580 A32 Cl 4-OMe-phenyl OCH₂ 2-quinoline — H, H — — H 581 A32Cl 4-pyrazolyl OCH₂ 2-quinoline — H, H — — H 582 A32 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — H, H — — H 583 A32 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — H, H — — H 584 A32 Cl

OCH₂ 2-quinoline — H, H — — H 585 A1  CN 4-pyridinyl OCH₂ 2-quinoline —— H H — 586 A1  CN 4-OMe-phenyl OCH₂ 2-quinoline — — H H — 587 A1  CN4-pyrazolyl OCH₂ 2-quinoline — — H H — 588 A1  CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H — 589 A1  CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H — 590 A1  CN

OCH₂ 2-quinoline — — H H — 591 A1  CN

OCH₂ 2-quinoline — — H H — 592 A1  CN

OCH₂ 2-quinoline — — H H — 593 A1  CN

OCH₂ 2-quinoline — — H H — 594 A1  CN

OCH₂ 2-quinoline — — H H — 595 A1  CN

OCH₂ 2-quinoline — — H H — 596 A1  CN

OCH₂ 2-quinoline — — H H — 597 A1  CN

OCH₂ 2-quinoline — — H H — 598 A2  CN 4-pyridinyl OCH₂ 2-quinoline — — HH H 599 A2  CN 4-pyridinyl OCH₂ 2-quinoline — — H H Me 601 A2  CN4-OMe-phenyl OCH₂ 2-quinoline — — H H H 602 A2  CN 4-OMe-phenyl OCH₂2-quinoline — — H H Me 604 A2  CN 4-pyrazolyl OCH₂ 2-quinoline — — H H H605 A2  CN 4-pyrazolyl OCH₂ 2-quinoline — — H H Me 607 A2  CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H H 608 A2  CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H Me 610 A2  CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H H 611 A2  CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H Me 613 A2  CN

OCH₂ 2-quinoline — — H H H 614 A2  CN

OCH₂ 2-quinoline — — H H Me 616 A2  CN

OCH₂ 2-quinoline — — H H H 617 A2  CN

OCH₂ 2-quinoline — — H H Me 619 A2  CN

OCH₂ 2-quinoline — — H H H 620 A2  CN

OCH₂ 2-quinoline — — H H Me 622 A2  CN

OCH₂ 2-quinoline — — H H H 623 A2  CN

OCH₂ 2-quinoline — — H H Me 625 A2  CN

OCH₂ 2-quinoline — — H H H 626 A2  CN

OCH₂ 2-quinoline — — H H Me 628 A2  CN

OCH₂ 2-quinoline — — H H H 629 A2  CN

OCH₂ 2-quinoline — — H H Me 631 A2  CN

OCH₂ 2-quinoline — — H H H 632 A2  CN

OCH₂ 2-quinoline — — H H Me 634 A2  CN

OCH₂ 2-quinoline — — H H H 635 A2  CN

OCH₂ 2-quinoline — — H H Me 637 A6  CN 4-pyridinyl OCH₂ 2-quinoline H, —— — — H 638 A6  CN 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — H 639 A6  CN4-pyrazolyl OCH₂ 2-quinoline H, — — — — H 640 A6  CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — H 641 A6  CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — H 642 A6  CN

OCH₂ 2-quinoline H, — — — — H 643 A6  CN

OCH₂ 2-quinoline H, — — — — H 644 A6  CN

OCH₂ 2-quinoline H, — — — — H 645 A6  CN

OCH₂ 2-quinoline H, — — — — H 646 A6  CN

OCH₂ 2-quinoline H, — — — — H 647 A6  CN

OCH₂ 2-quinoline H, — — — — H 648 A6  CN

OCH₂ 2-quinoline H, — — — — H 649 A6  CN

OCH₂ 2-quinoline H, — — — — H 650 A11 CN 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 651 A11 CN 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 652 A11CN 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 653 A11 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 654 A11 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 655 A11 CN

OCH₂ 2-quinoline H, — — — — — 656 A11 CN

OCH₂ 2-quinoline H, — — — — — 657 A11 CN

OCH₂ 2-quinoline H, — — — — — 658 A11 CN

OCH₂ 2-quinoline H, — — — — — 659 A11 CN

OCH₂ 2-quinoline H, — — — — — 660 A11 CN

OCH₂ 2-quinoline H, — — — — — 661 A11 CN

OCH₂ 2-quinoline H, — — — — — 662 A11 CN

OCH₂ 2-quinoline H, — — — — — 663 A12 CN 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 664 A12 CN 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 665 A12CN 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 666 A12 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 667 A12 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 668 A12 CN

OCH₂ 2-quinoline H, — — — — — 669 A12 CN

OCH₂ 2-quinoline H, — — — — — 670 A12 CN

OCH₂ 2-quinoline H, — — — — — 671 A12 CN

OCH₂ 2-quinoline H, — — — — — 672 A12 CN

OCH₂ 2-quinoline H, — — — — — 673 A12 CN

OCH₂ 2-quinoline H, — — — — — 674 A12 CN

OCH₂ 2-quinoline H, — — — — — 675 A12 CN

OCH₂ 2-quinoline H, — — — — — 676 A13 CN 4-pyridinyl OCH₂ 2-quinoline H,H — — — — 677 A13 CN 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 678 A13CN 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 679 A13 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 680 A13 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 681 A13 CN

OCH₂ 2-quinoline H, H — — — — 682 A13 CN

OCH₂ 2-quinoline H, H — — — — 683 A13 CN

OCH₂ 2-quinoline H, H — — — — 684 A13 CN

OCH₂ 2-quinoline H, H — — — — 685 A13 CN

OCH₂ 2-quinoline H, H — — — — 686 A13 CN

OCH₂ 2-quinoline H, H — — — — 687 A13 CN

OCH₂ 2-quinoline H, H — — — — 688 A13 CN

OCH₂ 2-quinoline H, H — — — — 689 A14 CN 4-pyridinyl OCH₂ 2-quinoline H,H — — — — 690 A14 CN 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 691 A14CN 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 692 A14 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 693 A14 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 694 A14 CN

OCH₂ 2-quinoline H, H — — — — 695 A14 CN

OCH₂ 2-quinoline H, H — — — — 696 A14 CN

OCH₂ 2-quinoline H, H — — — — 697 A14 CN

OCH₂ 2-quinoline H, H — — — — 698 A14 CN

OCH₂ 2-quinoline H, H — — — — 699 A14 CN

OCH₂ 2-quinoline H, H — — — — 700 A14 CN

OCH₂ 2-quinoline H, H — — — — 701 A14 CN

OCH₂ 2-quinoline H, H — — — — 702 A15 CN 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 703 A15 CN 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 704 A15CN 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 705 A15 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 706 A15 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 707 A15 CN

OCH₂ 2-quinoline H, — — — — — 708 A15 CN

OCH₂ 2-quinoline H, — — — — — 709 A15 CN

OCH₂ 2-quinoline H, — — — — — 710 A15 CN

OCH₂ 2-quinoline H, — — — — — 711 A15 CN

OCH₂ 2-quinoline H, — — — — — 712 A15 CN

OCH₂ 2-quinoline H, — — — — — 713 A15 CN

OCH₂ 2-quinoline H, — — — — — 714 A15 CN

OCH₂ 2-quinoline H, — — — — — 715 A19 CN 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 716 A19 CN 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 717 A19CN 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 718 A19 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 719 A19 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 720 A19 CN

OCH₂ 2-quinoline H, — — — — — 721 A19 CN

OCH₂ 2-quinoline H, — — — — — 722 A19 CN

OCH₂ 2-quinoline H, — — — — — 723 A19 CN

OCH₂ 2-quinoline H, — — — — — 724 A19 CN

OCH₂ 2-quinoline H, — — — — — 725 A19 CN

OCH₂ 2-quinoline H, — — — — — 726 A19 CN

OCH₂ 2-quinoline H, — — — — — 727 A19 CN

OCH₂ 2-quinoline H, — — — — — 728 A20 CN 4-pyridinyl OCH₂ 2-quinoline H,H — — — — 729 A20 CN 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 730 A20CN 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 731 A20 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 732 A20 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 733 A20 CN

OCH₂ 2-quinoline H, H — — — — 734 A20 CN

OCH₂ 2-quinoline H, H — — — — 735 A20 CN

OCH₂ 2-quinoline H, H — — — — 736 A20 CN

OCH₂ 2-quinoline H, H — — — — 737 A20 CN

OCH₂ 2-quinoline H, H — — — — 738 A20 CN

OCH₂ 2-quinoline H, H — — — — 739 A20 CN

OCH₂ 2-quinoline H, H — — — — 740 A20 CN

OCH₂ 2-quinoline H, H — — — — 741 A32 CN 4-pyridinyl OCH₂ 2-quinoline —H, H — — H 742 A32 CN 4-OMe-phenyl OCH₂ 2-quinoline — H, H — — H 743 A32CN 4-pyrazolyl OCH₂ 2-quinoline — H, H — — H 744 A32 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — H, H — — H 745 A32 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — H, H — — H 746 A32 CN

OCH₂ 2-quinoline — H, H — — H 747 A32 CN

OCH₂ 2-quinoline — H, H — — 748 A32 CN

OCH₂ 2-quinoline — H, H — — H 749 A32 CN

OCH₂ 2-quinoline — H, H — — H 750 A32 CN

OCH₂ 2-quinoline — H, H — — H 751 A32 CN

OCH₂ 2-quinoline — H, H — — H 752 A32 CN

OCH₂ 2-quinoline — H, H — — H 753 A32 CN

OCH₂ 2-quinoline — H, H — — H 1102 A13 Cl 4-pyrazolyl OCH₂ 2-quinolineMe, H — — — — 1103 A13 Cl 3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline Me,H — — — — 1104 A13 Cl 4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline Me, H —— — — 1105 A13 Cl

OCH₂ 2-quinoline Me, H — — — — 1106 A13 Cl

OCH₂ 2-quinoline Me, H — — — — 1107 A13 Cl

OCH₂ 2-quinoline Me, H — — — — 1108 A13 Cl

OCH₂ 2-quinoline Me, H — — — — 1109 A13 Cl

OCH₂ 2-quinoline Me, H — — — — 1110 A13 Cl

OCH₂ 2-quinoline Me, H — — — — 1111 A13 Cl

OCH₂ 2-quinoline Me, H — — — — 1112 A13 Cl

OCH₂ 2-quinoline Me, H — — — —

In a further aspect the compounds of the disclosure are embodied in withdistinct examples listed in the table below taken from Formula (III):

Ex. # HET W X Y Z R_(1a), R_(1b) R₂ R₃ R₄ R₇ 754 A1 Cl 4-pyridinyl OCH₂2-quinoline — — H H — 755 A1 Cl 4-OMe-phenyl OCH₂ 2-quinoline — — H H —756 A1 Cl 4-pyrazolyl OCH₂ 2-quinoline — — H H — 757 A1 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H — 758 A1 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H — 759 A1 Cl

OCH₂ 2-quinoline — — H H — 760 A1 Cl

OCH₂ 2-quinoline — — H H — 761 A1 Cl

OCH₂ 2-quinoline — — H H — 762 A1 Cl

OCH₂ 2-quinoline — — H H — 763 A1 Cl

OCH₂ 2-quinoline — — H H — 764 A1 Cl

OCH₂ 2-quinoline — — H H — 765 A1 Cl

OCH₂ 2-quinoline — — H H — 766 A1 Cl

OCH₂ 2-quinoline — — H H — 767 A2 Cl 4-pyridinyl OCH₂ 2-quinoline — — HH H 768 A2 Cl 4-pyridinyl OCH₂ 2-quinoline — — H H Me 770 A2 Cl4-OMe-phenyl OCH₂ 2-quinoline — — H H H 771 A2 Cl 4-OMe-phenyl OCH₂2-quinoline — — H H Me 773 A2 Cl 4-pyrazolyl OCH₂ 2-quinoline — — H H H774 A2 Cl 4-pyrazolyl OCH₂ 2-quinoline — — H H Me 776 A2 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H H 777 A2 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H Me 779 A2 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H H 780 A2 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H Me 782 A2 Cl

OCH₂ 2-quinoline — — H H H 783 A2 Cl

OCH₂ 2-quinoline — — H H Me 785 A2 Cl

OCH₂ 2-quinoline — — H H H 786 A2 Cl

OCH₂ 2-quinoline — — H H Me 788 A2 Cl

OCH₂ 2-quinoline — — H H H 789 A2 Cl

OCH₂ 2-quinoline — — H H Me 791 A2 Cl

OCH₂ 2-quinoline — — H H H 792 A2 Cl

OCH₂ 2-quinoline — — H H Me 794 A2 Cl

OCH₂ 2-quinoline — — H H H 795 A2 Cl

OCH₂ 2-quinoline — — H H Me 797 A2 Cl

OCH₂ 2-quinoline — — H H H 798 A2 Cl

OCH₂ 2-quinoline — — H H Me 800 A2 Cl

OCH₂ 2-quinoline — — H H H 801 A2 Cl

OCH₂ 2-quinoline — — H H Me 803 A2 Cl

OCH₂ 2-quinoline — — H H H 804 A2 Cl

OCH₂ 2-quinoline — — H H Me 806 A6 Cl 4-pyridinyl OCH₂ 2-quinoline H, —— — — H 807 A6 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — H 808 A6 Cl4-pyrazolyl OCH₂ 2-quinoline H, — — — — H 809 A6 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — H 810 A6 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — H 811 A6 Cl

OCH₂ 2-quinoline H, — — — — H 812 A6 Cl

OCH₂ 2-quinoline H, — — — — H 813 A6 Cl

OCH₂ 2-quinoline H, — — — — H 814 A6 Cl

OCH₂ 2-quinoline H, — — — — H 815 A6 Cl

OCH₂ 2-quinoline H, — — — — H 816 A6 Cl

OCH₂ 2-quinoline H, — — — — H 817 A6 Cl

OCH₂ 2-quinoline H, — — — — H 818 A6 Cl

OCH₂ 2-quinoline H, — — — — H 819 A11 Cl 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 820 A11 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 821 A11Cl 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 822 A11 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 823 A11 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 824 A11 Cl

OCH₂ 2-quinoline H, — — — — — 825 A11 Cl

OCH₂ 2-quinoline H, — — — — — 826 A11 Cl

OCH₂ 2-quinoline H, — — — — — 827 A11 Cl

OCH₂ 2-quinoline H, — — — — — 828 A11 Cl

OCH₂ 2-quinoline H, — — — — — 829 A11 Cl

OCH₂ 2-quinoline H, — — — — — 830 A11 Cl

OCH₂ 2-quinoline H, — — — — — 831 A11 Cl

OCH₂ 2-quinoline H, — — — — — 832 A12 Cl 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 833 A12 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 834 A12Cl 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 835 A12 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 836 A12 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 837 A12 Cl

OCH₂ 2-quinoline H, — — — — — 838 A12 Cl

OCH₂ 2-quinoline H, — — — — — 839 A12 Cl

OCH₂ 2-quinoline H, — — — — — 840 A12 Cl

OCH₂ 2-quinoline H, — — — — — 841 A12 Cl

OCH₂ 2-quinoline H, — — — — — 842 A12 Cl

OCH₂ 2-quinoline H, — — — — — 843 A12 Cl

OCH₂ 2-quinoline H, — — — — — 844 A12 Cl

OCH₂ 2-quinoline H, — — — — — 845 A13 Cl 4-pyridinyl OCH₂ 2-quinoline H,H — — — — 846 A13 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 847 A13Cl 4-pyrazolyl OCH₂ 2-quinoline H — — — — 848 A13 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 849 A13 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 850 A13 Cl

OCH₂ 2-quinoline H, H — — — — 851 A13 Cl

OCH₂ 2-quinoline H, H — — — — 852 A13 Cl

OCH₂ 2-quinoline H, H — — — — 853 A13 Cl

OCH₂ 2-quinoline H, H — — — — 854 A13 Cl

OCH₂ 2-quinoline H, H — — — — 855 A13 Cl

OCH₂ 2-quinoline H, H — — — — 856 A13 Cl

OCH₂ 2-quinoline H, H — — — — 857 A13 Cl

OCH₂ 2-quinoline H, H — — — — 858 A14 Cl 4-pyridinyl OCH₂ 2-quinoline H,H — — — — 859 A14 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 860 A14Cl 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 861 A14 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 862 A14 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 863 A14 Cl

OCH₂ 2-quinoline H, H — — — — 864 A14 Cl

OCH₂ 2-quinoline H, H — — — — 865 A14 Cl

OCH₂ 2-quinoline H, H — — — — 866 A14 Cl

OCH₂ 2-quinoline H, H — — — — 867 A14 Cl

OCH₂ 2-quinoline H, H — — — — 868 A14 Cl

OCH₂ 2-quinoline H, H — — — — 869 A14 Cl

OCH₂ 2-quinoline H, H — — — — 870 A14 Cl

OCH₂ 2-quinoline H, H — — — — 871 A15 Cl 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 872 A15 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 873 A15Cl 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 874 A15 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 875 A15 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 876 A15 Cl

OCH₂ 2-quinoline H, — — — — — 877 A15 Cl

OCH₂ 2-quinoline H, — — — — — 878 A15 Cl

OCH₂ 2-quinoline H, — — — — — 879 A15 Cl

OCH₂ 2-quinoline H, — — — — — 880 A15 Cl

OCH₂ 2-quinoline H, — — — — — 881 A15 Cl

OCH₂ 2-quinoline H, — — — — — 882 A15 Cl

OCH₂ 2-quinoline H, — — — — — 883 A15 Cl

OCH₂ 2-quinoline H, — — — — — 884 A19 Cl 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 885 A19 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 886 A19Cl 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 887 A19 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 888 A19 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 889 A19 Cl

OCH₂ 2-quinoline H, — — — — — 890 A19 Cl

OCH₂ 2-quinoline H, — — — — — 891 A19 Cl

OCH₂ 2-quinoline H, — — — — — 892 A19 Cl

OCH₂ 2-quinoline H, — — — — — 893 A19 Cl

OCH₂ 2-quinoline H, — — — — — 894 A19 Cl

OCH₂ 2-quinoline H, — — — — — 895 A19 Cl

OCH₂ 2-quinoline H, — — — — — 896 A19 Cl

OCH₂ 2-quinoline H, — — — — — 897 A20 Cl 4-pyridinyl OCH₂ 2-quinoline H,H — — — — 898 A20 Cl 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 899 A20Cl 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 900 A20 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 901 A20 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 902 A20 Cl

OCH₂ 2-quinoline H, H — — — — 903 A20 Cl

OCH₂ 2-quinoline H, H — — — — 904 A20 Cl

OCH₂ 2-quinoline H, H — — — — 905 A20 Cl

OCH₂ 2-quinoline H, H — — — — 906 A20 Cl

OCH₂ 2-quinoline H, H — — — — 907 A20 Cl

OCH₂ 2-quinoline H, H — — — — 908 A20 Cl

OCH₂ 2-quinoline H, H — — — — 909 A20 Cl

OCH₂ 2-quinoline H, H — — — — 910 A32 Cl 4-pyridinyl OCH₂ 2-quinoline —H, H — — H 911 A32 Cl 4-OMe-phenyl OCH₂ 2-quinoline — H, H — — H 912 A32Cl 4-pyrazolyl OCH₂ 2-quinoline — H, H — — H 913 A32 Cl3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — H, H — — H 914 A32 Cl4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — H, H — — H 915 A32 Cl

OCH₂ 2-quinoline — H, H — — H 916 A1 CN 4-pyridinyl OCH₂ 2-quinoline — —H H — 917 A1 CN 4-OMe-phenyl OCH₂ 2-quinoline — — H H — 918 A1 CN4-pyrazolyl OCH₂ 2-quinoline — — H H — 919 A1 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H — 920 A1 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H — 921 A1 CN

OCH₂ 2-quinoline — — H H — 922 A1 CN

OCH₂ 2-quinoline — — H H — 923 A1 CN

OCH₂ 2-quinoline — — H H — 924 A1 CN

OCH₂ 2-quinoline — — H H — 925 A1 CN

OCH₂ 2-quinoline — — H H — 926 A1 CN

OCH₂ 2-quinoline — — H H — 927 A1 CN

OCH₂ 2-quinoline — — H H — 928 A1 CN

OCH₂ 2-quinoline — — H H — 929 A2 CN 4-pyridinyl OCH₂ 2-quinoline — — HH H 930 A2 CN 4-pyridinyl OCH₂ 2-quinoline — — H H Me 932 A2 CN4-OMe-phenyl OCH₂ 2-quinoline — — H H H 933 A2 CN 4-OMe-phenyl OCH₂2-quinoline — — H H Me 935 A2 CN 4-pyrazolyl OCH₂ 2-quinoline — — H H H936 A2 CN 4-pyrazolyl OCH₂ 2-quinoline — — H H Me 938 A2 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H H 939 A2 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H Me 941 A2 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H H 942 A2 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — — H H Me 944 A2 CN

OCH₂ 2-quinoline — — H H H 945 A2 CN

OCH₂ 2-quinoline — — H H Me 947 A2 CN

OCH₂ 2-quinoline — — H H H 948 A2 CN

OCH₂ 2-quinoline — — H H Me 950 A2 CN

OCH₂ 2-quinoline — — H H H 951 A2 CN

OCH₂ 2-quinoline — — H H Me 953 A2 CN

OCH₂ 2-quinoline — — H H H 954 A2 CN

OCH₂ 2-quinoline — — H H Me 956 A2 CN

OCH₂ 2-quinoline — — H H H 957 A2 CN

OCH₂ 2-quinoline — — H H Me 959 A2 CN

OCH₂ 2-quinoline — — H H H 960 A2 CN

OCH₂ 2-quinoline — — H H Me 962 A2 CN

OCH₂ 2-quinoline — — H H H 963 A2 CN

OCH₂ 2-quinoline — — H H Me 965 A2 CN

OCH₂ 2-quinoline — — H H H 966 A2 CN

OCH₂ 2-quinoline — — H H Me 968 A6 CN 4-pyridinyl OCH₂ 2-quinoline H, —— — — H 969 A6 CN 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — H 970 A6 CN4-pyrazolyl OCH₂ 2-quinoline H, — — — — H 971 A6 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — H 972 A6 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — H 973 A6 CN

OCH₂ 2-quinoline H, — — — — H 974 A6 CN

OCH₂ 2-quinoline H, — — — — H 975 A6 CN

OCH₂ 2-quinoline H, — — — — H 976 A6 CN

OCH₂ 2-quinoline H, — — — — H 977 A6 CN

OCH₂ 2-quinoline H, — — — — H 978 A6 CN

OCH₂ 2-quinoline H, — — — — H 979 A6 CN

OCH₂ 2-quinoline H, — — — — H 980 A6 CN

OCH₂ 2-quinoline H, — — — — H 981 A11 CN 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 982 A11 CN 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 983 A11CN 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 984 A11 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 985 A11 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 986 A11 CN

OCH₂ 2-quinoline H, — — — — — 987 A11 CN

OCH₂ 2-quinoline H, — — — — — 988 A11 CN

OCH₂ 2-quinoline H, — — — — — 989 A11 CN

OCH₂ 2-quinoline H, — — — — — 990 A11 CN

OCH₂ 2-quinoline H, — — — — — 991 A11 CN

OCH₂ 2-quinoline H, — — — — — 992 A11 CN

OCH₂ 2-quinoline H, — — — — — 993 A11 CN

OCH₂ 2-quinoline H, — — — — — 994 A12 CN 4-pyridinyl OCH₂ 2-quinoline H,— — — — — 995 A12 CN 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 996 A12CN 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 997 A12 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 998 A12 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 999 A12 CN

OCH₂ 2-quinoline H, — — — — — 1000 A12 CN

OCH₂ 2-quinoline H, — — — — — 1001 A12 CN

OCH₂ 2-quinoline H, — — — — — 1002 A12 CN

OCH₂ 2-quinoline H, — — — — — 1003 A12 CN

OCH₂ 2-quinoline H, — — — — — 1004 A12 CN

OCH₂ 2-quinoline H, — — — — — 1005 A12 CN

OCH₂ 2-quinoline H, — — — — — 1006 A12 CN

OCH₂ 2-quinoline H, — — — — — 1007 A13 CN 4-pyridinyl OCH₂ 2-quinolineH, H — — — — 1008 A13 CN 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 1009A13 CN 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 1010 A13 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 1011 A13 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 1012 A13 CN

OCH₂ 2-quinoline H, H — — — — 1013 A13 CN

OCH₂ 2-quinoline H, H — — — — 1014 A13 CN

OCH₂ 2-quinoline H, H — — — — 1015 A13 CN

OCH₂ 2-quinoline H, H — — — — 1016 A13 CN

OCH₂ 2-quinoline H, H — — — — 1017 A13 CN

OCH₂ 2-quinoline H, H — — — — 1018 A13 CN

OCH₂ 2-quinoline H, H — — — — 1019 A13 CN

OCH₂ 2-quinoline H, H — — — — 1020 A14 CN 4-pyridinyl OCH₂ 2-quinolineH, H — — — — 1021 A14 CN 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 1022A14 CN 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 1023 A14 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 1024 A14 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 1025 A14 CN

OCH₂ 2-quinoline H, H — — — — 1026 A14 CN

OCH₂ 2-quinoline H, H — — — — 1027 A14 CN

OCH₂ 2-quinoline H, H — — — — 1028 A14 CN

OCH₂ 2-quinoline H, H — — — — 1029 A14 CN

OCH₂ 2-quinoline H, H — — — — 1030 A14 CN

OCH₂ 2-quinoline H, H — — — — 1031 A14 CN

OCH₂ 2-quinoline H, H — — — — 1032 A14 CN

OCH₂ 2-quinoline H, H — — — — 1033 A15 CN 4-pyridinyl OCH₂ 2-quinolineH, — — — — — 1034 A15 CN 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 1035A15 CN 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 1036 A15 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 1037 A15 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 1038 A15 CN

OCH₂ 2-quinoline H, — — — — — 1039 A15 CN

OCH₂ 2-quinoline H, — — — — — 1040 A15 CN

OCH₂ 2-quinoline H, — — — — — 1041 A15 CN

OCH₂ 2-quinoline H, — — — — — 1042 A15 CN

OCH₂ 2-quinoline H, — — — — — 1043 A15 CN

OCH₂ 2-quinoline H, — — — — — 1044 A15 CN

OCH₂ 2-quinoline H, — — — — — 1045 A15 CN

OCH₂ 2-quinoline H, — — — — — 1046 A19 CN 4-pyridinyl OCH₂ 2-quinolineH, — — — — — 1047 A19 CN 4-OMe-phenyl OCH₂ 2-quinoline H, — — — — — 1048A19 CN 4-pyrazolyl OCH₂ 2-quinoline H, — — — — — 1049 A19 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 1050 A19 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, — — — — — 1051 A19 CN

OCH₂ 2-quinoline H, — — — — — 1052 A19 CN

OCH₂ 2-quinoline H, — — — — — 1053 A19 CN

OCH₂ 2-quinoline H, — — — — — 1054 A19 CN

OCH₂ 2-quinoline H, — — — — — 1055 A19 CN

OCH₂ 2-quinoline H, — — — — — 1056 A19 CN

OCH₂ 2-quinoline H, — — — — — 1057 A19 CN

OCH₂ 2-quinoline H, — — — — — 1058 A19 CN

OCH₂ 2-quinoline H, — — — — — 1059 A20 CN 4-pyridinyl OCH₂ 2-quinolineH, H — — — — 1060 A20 CN 4-OMe-phenyl OCH₂ 2-quinoline H, H — — — — 1061A20 CN 4-pyrazolyl OCH₂ 2-quinoline H, H — — — — 1062 A20 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 1063 A20 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline H, H — — — — 1064 A20 CN

OCH₂ 2-quinoline H, H — — — — 1065 A20 CN

OCH₂ 2-quinoline H, H — — — — 1066 A20 CN

OCH₂ 2-quinoline H, H — — — — 1067 A20 CN

OCH₂ 2-quinoline H, H — — — — 1068 A20 CN

OCH₂ 2-quinoline H, H — — — — 1069 A20 CN

OCH₂ 2-quinoline H, H — — — — 1070 A20 CN

OCH₂ 2-quinoline H, H — — — — 1071 A20 CN

OCH₂ 2-quinoline H, H — — — — 1072 A32 CN 4-pyridinyl OCH₂ 2-quinoline —H, H — — H 1073 A32 CN 4-OMe-phenyl OCH₂ 2-quinoline — H, H — — H 1074A32 CN 4-pyrazolyl OCH₂ 2-quinoline — H, H — — H 1075 A32 CN3-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — H, H — — H 1076 A32 CN4-(1-methyl-1H-pyrazolyl) OCH₂ 2-quinoline — H, H — — H 1077 A32 CN

OCH₂ 2-quinoline — H, H — — H 1078 A32 CN

OCH₂ 2-quinoline — H, H — — H 1079 A32 CN

OCH₂ 2-quinoline — H, H — — H 1080 A32 CN

OCH₂ 2-quinoline — H, H — — H 1081 A32 CN

OCH₂ 2-quinoline — H, H — — H 1082 A32 CN

OCH₂ 2-quinoline — H, H — — H 1083 A32 CN

OCH₂ 2-quinoline — H, H — — H 1084 A32 CN

OCH₂ 2-quinoline — H, H — — H 1099 A7 Cl

OCH₂ 2-quinoline — — H H —

Dosage and Administration

The present disclosure includes pharmaceutical composition for treatinga subject having a neurological disorder comprising a therapeuticallyeffective amount of a compound of Formulas (I), (II) and (III), aderivative or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient, carrier or diluent. Thepharmaceutical compositions can be administered in a variety of dosageforms including, but not limited to, a solid dosage form or in a liquiddosage form, an oral dosage form, a parenteral dosage form, anintranasal dosage form, a suppository, a lozenge, a troche, buccal, acontrolled release dosage form, a pulsed release dosage form, animmediate release dosage form, an intravenous solution, a suspension orcombinations thereof. The dosage can be an oral dosage form that is acontrolled release dosage form. The oral dosage form can be a tablet ora caplet. The compounds can be administered, for example, by oral orparenteral routes, including intravenous, intramuscular,intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal,vaginal and topical (including buccal and sublingual) administration. Inone embodiment, the compounds or pharmaceutical compositions comprisingthe compounds are delivered to a desired site, such as the brain, bycontinuous injection via a shunt.

In another embodiment, the compound can be administered parenterally,such as intravenous (IV) administration. The formulations foradministration will commonly comprise a solution of the compound of theFormulas (I), (II) and (III) dissolved in a pharmaceutically acceptablecarrier. Among the acceptable vehicles and solvents that can be employedare water and Ringer's solution, an isotonic sodium chloride. Inaddition, sterile fixed oils can conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid can likewise be used in the preparation ofinjectables. These solutions are sterile and generally free ofundesirable matter. These formulations may be sterilized byconventional, well known sterilization techniques. The formulations maycontain pharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions such as pH adjusting and bufferingagents, toxicity adjusting agents, e.g., sodium acetate, sodiumchloride, potassium chloride, calcium chloride, sodium lactate and thelike. The concentration of compound of Formulas (I), (II) and (III) inthese formulations can vary widely, and will be selected primarily basedon fluid volumes, viscosities, body weight, and the like, in accordancewith the particular mode of administration selected and the patient'sneeds. For IV administration, the formulation can be a sterileinjectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension can be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation can also be asterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

In one embodiment, a compound of Formulas (I), (II) and (III) can beadministered by introduction into the central nervous system of thesubject, e.g., into the cerbrospinal fluid of the subject. Theformulations for administration will commonly comprise a solution of thecompound of Formulas (I), (II) and (III) dissolved in a pharmaceuticallyacceptable carrier. In certain aspects, the compound of Formulas (I),(II) and (III) is introduced intrathecally, e.g., into a cerebralventricle, the lumbar area, or the cisterna magna. In another aspect,the compound of Formulas (I), (II) and (III) is introducedintraocularly, to thereby contact retinal ganglion cells.

The pharmaceutically acceptable formulations can easily be suspended inaqueous vehicles and introduced through conventional hypodermic needlesor using infusion pumps. Prior to introduction, the formulations can besterilized with, preferably, gamma radiation or electron beamsterilization.

In one embodiment, the pharmaceutical composition comprising a compoundof Formulas (I), (II) and (III) is administered into a subjectintrathecally. As used herein, the term “intrathecal administration” isintended to include delivering a pharmaceutical composition comprising acompound of Formulas (I), (II) and (III) directly into the cerebrospinalfluid of a subject, by techniques including lateral cerebroventricularinjection through a burrhole or cisternal or lumbar puncture or the like(described in Lazorthes et al. Advances in Drug Delivery Systems andApplications in Neurosurgery, 143-192 and Omaya et al., Cancer DrugDelivery, 1: 169-179, the contents of which are incorporated herein byreference). The term “lumbar region” is intended to include the areabetween the third and fourth lumbar (lower back) vertebrae. The term“cisterna magna” is intended to include the area where the skull endsand the spinal cord begins at the back of the head. The term “cerebralventricle” is intended to include the cavities in the brain that arecontinuous with the central canal of the spinal cord. Administration ofa compound of Formulas (I), (II) and (III) to any of the above mentionedsites can be achieved by direct injection of the pharmaceuticalcomposition comprising the compound of Formulas (I), (II) and (III) orby the use of infusion pumps. For injection, the pharmaceuticalcompositions can be formulated in liquid solutions, preferably inphysiologically compatible buffers such as Hank's solution or Ringer'ssolution. In addition, the pharmaceutical compositions may be formulatedin solid form and re-dissolved or suspended immediately prior to use.Lyophilized forms are also included. The injection can be, for example,in the form of a bolus injection or continuous infusion (e.g., usinginfusion pumps) of pharmaceutical composition.

In one embodiment, the pharmaceutical composition comprising a compoundof Formulas (I), (II) and (III) is administered by lateral cerebroventricular injection into the brain of a subject. The injection can bemade, for example, through a burr hole made in the subject's skull. Inanother embodiment, the encapsulated therapeutic agent is administeredthrough a surgically inserted shunt into the cerebral ventricle of asubject. For example, the injection can be made into the lateralventricles, which are larger, even though injection into the third andfourth smaller ventricles can also be made.

In yet another embodiment, the pharmaceutical composition isadministered by injection into the cisterna magna, or lumbar area of asubject.

For oral administration, the compounds will generally be provided inunit dosage forms of a tablet, pill, dragee, lozenge or capsule; as apowder or granules; or as an aqueous solution, suspension, liquid, gels,syrup, slurry, etc. suitable for ingestion by the patient. Tablets fororal use may include the active ingredients mixed with pharmaceuticallyacceptable excipients such as inert diluents, disintegrating agents,binding agents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservatives. Suitable inert diluents includesodium and calcium carbonate, sodium and calcium phosphate, and lactose,while corn starch and alginic acid are suitable disintegrating agents.Binding agents may include starch and gelatin, while the lubricatingagent, if present, will generally be magnesium stearate, stearic acid ortalc. If desired, the tablets may be coated with a material such asglyceryl monostearate or glyceryl distearate, to delay absorption in thegastrointestinal tract.

Pharmaceutical preparations for oral use can be obtained throughcombination of a compound of Formulas (I), (II) and (III) with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable additional compounds, ifdesired, to obtain tablets or dragee cores. Suitable solid excipients inaddition to those previously mentioned are carbohydrate or proteinfillers that include, but are not limited to, sugars, including lactose,sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato,or other plants; cellulose such as methyl cellulose,hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gumsincluding arabic and tragacanth; as well as proteins such as gelatin andcollagen. If desired, disintegrating or solubilizing agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, alginicacid, or a salt thereof, such as sodium alginate.

Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid diluent, and soft gelatin capsuleswherein the active ingredients is mixed with water or an oil such aspeanut oil, liquid paraffin or olive oil. Dragee cores are provided withsuitable coatings. For this purpose, concentrated sugar solutions may beused, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide,lacquer solutions, and suitable organic solvents or solvent mixtures.Dyestuffs or pigments may be added to the tablets or dragee coatings foridentification or to characterize different combinations of activecompound doses.

For transmucosal administration (e.g., buccal, rectal, nasal, ocular,etc.), penetrants appropriate to the barrier to be permeated are used inthe formulation. Such penetrants are generally known in the art.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate. Formulations suitable for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations containing in addition to the active ingredient suchcarriers as are known in the art to be appropriate. For intramuscular,intraperitoneal, subcutaneous and intravenous use, the compounds willgenerally be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity. Suitable aqueous vehiclesinclude Ringer's solution and isotonic sodium chloride. Aqueoussuspensions may include suspending agents such as cellulose derivatives,sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wettingagent such as lecithin. Suitable preservatives for aqueous suspensionsinclude ethyl and n-propyl p-hydroxybenzoate.

The suppositories for rectal administration of the drug can be preparedby mixing the drug with a suitable non-irritating excipient which issolid at ordinary temperatures but liquid at the rectal temperatures andwill therefore melt in the rectum to release the drug. Such materialsare cocoa butter and polyethylene glycols.

The compounds can be delivered transdermally, by a topical route,formulated as applicator sticks, solutions, suspensions, emulsions,gels, creams, ointments, pastes, jellies, paints, powders, or aerosols.

The compounds may also be presented as aqueous or liposome formulations.Aqueous suspensions can contain a compound of Formulas (I), (II) and(III) in admixture with excipients suitable for the manufacture ofaqueous suspensions. Such excipients include a suspending agent, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethylene oxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensationproduct of ethylene oxide with a partial ester derived from fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Oil suspensions can be formulated by suspending a compound of Formulas(I), (II) and (III) in a vegetable oil, such as arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin;or a mixture of these. The oil suspensions can contain a thickeningagent, such as beeswax, hard paraffin or cetyl alcohol. Sweeteningagents can be added to provide a palatable oral preparation, such asglycerol, sorbitol or sucrose. These formulations can be preserved bythe addition of an antioxidant such as ascorbic acid. As an example ofan injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther.281:93-102, 1997. The pharmaceutical formulations can also be in theform of oil-in-water emulsions. The oily phase can be a vegetable oil ora mineral oil, described above, or a mixture of these. Suitableemulsifying agents include naturally-occurring gums, such as gum acaciaand gum tragacanth, naturally occurring phosphatides, such as soybeanlecithin, esters or partial esters derived from fatty acids and hexitolanhydrides, such as sorbitan mono-oleate, and condensation products ofthese partial esters with ethylene oxide, such as polyoxyethylenesorbitan mono-oleate. The emulsion can also contain sweetening agentsand flavoring agents, as in the formulation of syrups and elixirs. Suchformulations can also contain a demulcent, a preservative, or a coloringagent.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation or transcutaneous delivery (e.g.,subcutaneously or intramuscularly), intramuscular injection or atransdermal patch. Thus, for example, the compounds may be formulatedwith suitable polymeric or hydrophobic materials (e.g., as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

For administration by inhalation, the compounds are convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof e.g., gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

In general a suitable dose will be in the range of 0.01 to 100 mg perkilogram body weight of the recipient per day, preferably in the rangeof 0.1 to 10 mg per kilogram body weight per day. The desired dose ispreferably presented once daily, but may be dosed as two, three, four,five, six or more sub-doses administered at appropriate intervalsthroughout the day.

The compounds can be administered as the sole active agent, or incombination with other known therapeutics to be beneficial in thetreatment of neurological disorders. In any event, the administeringphysician can provide a method of treatment that is prophylactic ortherapeutic by adjusting the amount and timing of drug administration onthe basis of observations of one or more symptoms (e.g., motor orcognitive function as measured by standard clinical scales orassessments) of the disorder being treated. Details on techniques forformulation and administration are well described in the scientific andpatent literature, see, e.g., the latest edition of Remington'sPharmaceutical Sciences, Maack Publishing Co, Easton Pa. After apharmaceutical composition has been formulated in an acceptable carrier,it can be placed in an appropriate container and labeled for treatmentof an indicated condition. For administration of the compounds ofFormulas (I), (II) and (III), such labeling would include, e.g.,instructions concerning the amount, frequency and method ofadministration.

Biological Examples In Vivo Methods

Subjects: Male C57BL/6J mice (Charles River; 20-25 g) were used for allassays except prepulse inhibition (PPI) which used male DBA/2N mice(Charles River, 20-25 g). For all studies, animals were housed five/cageon a 12-h light/dark cycle with food and water available ad libitum.Conditioned avoidance responding: Testing was performed in commerciallyavailable avoidance boxes (Kinder Scientific, Poway Calif.). The boxeswere divided into two compartments separated by an archway. Each side ofthe chamber has electronic grid flooring that is equipped to administerfootshocks and an overhead light. Training consisted of repeatedpairings of the light (conditioned stimulus) followed by a shock(unconditioned stimulus). For each trial the light was presented for 5sec followed by a 0.5 mA shock that would terminate if the mouse crossedto the other chamber or after 10 seconds. The intertrial interval wasset to 20 seconds. Each training and test session consisted a four minhabituation period followed by 30 trials. The number of avoidances(mouse crossed to other side during presentation of the light,), escapes(mouse crossed to the other side during presentation of the shock) andfailures (mouse did not cross during the entire trial period) wererecorded by a computer. For study inclusion an animal had to reach acriterion of at least 80% avoidances for two consecutive test sessions.PPI: Mice were individually placed into the test chambers(StartleMonitor, Kinder Scientific, Poway Calif.). The animals weregiven a five min acclimation period to the test chambers with thebackground noise level set to 65 decibel (dB) which remained for theentire test session. Following acclimation, four successive trials 120dB pulse for 40 msec were presented, however these trials were notincluded in data analysis. The mice were then subjected to fivedifferent types of trials in random order: pulse alone (120 dB for 40msec), no stimulus and three different prepulse+pulse trials with theprepulse set at 67, 69 or 74 dB for 20 msec followed a 100 msec later bya120 dB pulse for 40 msec. Each animal received 12 trials for eachcondition for a total of 60 trials with an average intertrial intervalof 15 sec. Percent PPI was calculated according to the followingformula: (1-(startle response to prepulse+pulse)/startle response topulse alone))×100.MK-801-induced hyperactivity: After a 30 min acclimatation to the testroom mice were individually placed into test cages for a 30 minhabituation period. Following habituation to test cages, baselineactivity was recorded for 60 min. Mice were then briefly removed andadministered test compound and placed immediately back into the testcage. At 5 min prior to test time mice were again briefly removed fromtest cages and administered MK-801 (0.3 mg/kg, i.p. in 0.9% saline) andthen immediately placed back into test cages and activity level recorded1 hour. Activity level was measured as distance travelled in centimeters(Ethovision tracking software, Noldus Inc. Wageningen, Netherlands).Catalepsy: Mice were placed on a wire mesh screen set at a 60 degreeangle with their heads facing upwards and the latency to move or breakstance was recorded. Animals were given three trials per time point witha 30 sec cut-off per trial.Data analysis: A one-way or two-way ANOVA was used to evaluate overalldifferences between treatments and a Tukey's post-hoc test or Student'st-test was used to evaluate differences between treatment groups for theone-way ANOVA and a Bonferroni test was used for the two-way ANOVA. Thecriterion for statistical significance was set to p≦0.05.

In Vitro Methods

hPDE10A1 Enzyme Activity: 50 μl samples of serially diluted HumanPDE10A1 enzyme were incubated with 50 μl of [³H]-cAMP for 20 minutes (at37° C.). Reactions were carried out in Greiner 96 deep well 1 mlmaster-block. The enzyme was diluted in 20 mM Tris HCl pH7.4 and[³H]-cAMP was diluted in 10 mM MgCl₂, 40 mM Tris.HCl pH 7.4. Thereaction was terminated by denaturing the PDE enzyme (at 70° C.) afterwhich [³H]-5′-AMP was converted to [³H]-adenosine by adding 25 μl snakevenom nucleotidase and incubating for 10 minutes (at 37° C.). Adenosine,being neutral, was separated from charged cAMP or AMP by the addition of200 μl Dowex resin. Samples were shaken for 20 minutes then centrifugedfor 3 minutes at 2,500 r.p.m. 50 μl of supernatant was removed and addedto 200 μl of MicroScint-20 in white plates (Greiner 96-well Optiplate)and shaken for 30 minutes before reading on Perkin Elmer TopCountScintillation Counter.hPDE10A1 Enzyme Inhibition: To check inhibition profile 11 μl ofserially diluted inhibitor was added to 50 μl of [³H]-cAMP and 50 μl ofdiluted Human PDE10A1 and assay was carried out as in the enzymeactivity assay. Data was analysed using Prism software (GraphPad Inc).Representative compounds of this disclosure are shown in the tablebelow. A compound with the value “A” had an IC₅₀ value less than orequal to 50 nM. A compound with the value “B” had an IC₅₀ value greaterthan 50 nM:

hPDE10A1 Ex Name IC₅₀ Band 37 4-(pyridin-4-yl)-3-(4-(quinolin-2- Aylmethoxy)phenyl)furan-2(5H)-one 53 4-(3-fluoro-4-methoxyphenyl)-3-(4- A(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one 544-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin- A2-ylmethoxy)phenyl)furan-2(5H)-one 552-methoxy-5-(5-oxo-4-(4-(quinolin-2- Aylmethoxy)phenyl)-2,5-dihydrofuran-3-yl)benzonitrile 594-(4-methoxyphenyl)-3-(4-(quinolin-2- A ylmethoxy)phenyl)furan-2(5H)-one94 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2- Aylmethoxy)phenyl)-1H-pyrrol-2(5H)-one 1254-(4-methoxyphenyl)-1-methyl-3-(4-(quinolin-2- Aylmethoxy)phenyl)-1H-pyrrol-2(5H)-one 143-(4-methoxyphenyl)-4-(4-(quinolin-2- A ylmethoxy)phenyl)furan-2(5H)-one424 4-(2-chloro-4-(quinolin-2-ylmethoxy)phenyl)-3- B(4-methoxyphenyl)furan-2(5H)-one 1085 4-morpholino-3-(4-(quinolin-2- Bylmethoxy)phenyl)furan-2(5H)-one 1094 3-(pyridin-4-yl)-4-(4-(quinolin-2-A ylmethoxy)phenyl)isoxazol-5(2H)-one 10953-(4-methoxyphenyl)-4-(4-((6-methylpyridin-2- Byl)methoxy)phenyl)furan-2(5H)-one 10965-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)- B1H-pyrazol-3(2H)-one 1097 2-methyl-5-(pyridin-4-yl)-4-(4-(quinolin-2- Bylmethoxy)phenyl)-1H-pyrazol-3(2H)-one 10984-(pyridin-3-yl)-3-(4-(quinolin-2- B ylmethoxy)phenyl)furan-2(5H)-one1099 3-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)- B4-(pyridin-4-yl)furan-2(5H)-one

1. A compound of Formula (I) or (II) or (III) or pharmaceuticallyacceptable salt thereof

Wherein: HET is a heterocyclic ring selected from Formulas A1-A2, A6-A8,A10-A32 and A38 below

and the left most radical is connected to the X group; W is selectedfrom halogen, cyano, nitro, alkoxy, amino, alkylamino, dialkylamino,carboxy, amido, alkylamido, and dialkylamido; X is selected from C₃-C₈alkyl, optionally substituted C₃-C₆ cycloalkyl, optionally substitutedC₄-C₇ cycloalkylalkyl, optionally substituted heterocycloalkyl,optionally substituted heterocycloalkylalkyl, optionally substitutedaryl, optionally substituted arylalkyl, optionally substitutedheteroaryl and optionally substituted heteroarylalkyl; Y is a bond or adivalent linker group selected from —CH₂—, —O—, —SO₂—, —CH₂O—, —OCH₂—and —CH₂CH₂— with the rightmost radical of the Y group connected to theZ substituent; Z is optionally substituted heteroaryl; R_(1a) isselected from hydrogen, C₁-C₄ alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted C₄-C₇ cycloalkylalkyl and optionallysubstituted C₄-C₇ alkoxyalkyl with the proviso that when R_(1a) is nothydrogen, R_(1b) is hydrogen or that when R_(1b) is absent, R_(1a) mustbe hydrogen; R_(1b) is selected from hydrogen, C₁-C₄ alkyl, C₃-C₆optionally substituted cycloalkyl, optionally substituted C₄-C₇cycloalkylalkyl and optionally substituted C₄-C₇ alkoxyalkyl with theproviso that when R_(1b) is not hydrogen, R_(1a) is hydrogen; Each R₂ isindependently selected from hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted alkoxyalkyl with the provisothat at least one R₂ is hydrogen; R₃ and R₄ are independently selectedfrom hydrogen, C₁-C₄ alkyl, CF₃ and optionally substituted cycloalkylwith the proviso that at least one R₃ or R₄ group must be hydrogen; R₅is selected from alkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl and optionally substituted alkoxyalkyl; R₇is selected from hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl andoptionally substituted alkoxyalkyl; and n is independently selected from1 and
 2. 2-14. (canceled)
 15. The compound of claim 1 where Z is anoptionally substituted heteroaryl having only 6 ring atoms selected fromC and N provided the total number of ring nitrogens is less than orequal to two; said ring is optionally substituted with up to 2substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyloxy, C₄-C₇ cycloalkylalkyl,cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro. 16-22.(canceled)
 23. The compound of claim 1 where Z is selected from2-quinolinyl and 6-fluoroquinolin-2-yl.
 24. The compound of claim 1where Z is 2-quinolinyl.
 25. The compound of claim 1 where the Zsubstituent is unsubstituted. 26-44. (canceled)
 45. The compound ofclaim 1 where X is a heterocycloalkyl group selected from FormulasB1-B16 depicted below:

wherein R₆ is selected from hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl andC₄-C₇ cycloalkylalkyl. 46-56. (canceled)
 57. The compound of claim 1where X is selected from phenyl and pyridinyl.
 58. The compound of claim1 where X is restricted phenyl.
 59. The compound of claim 1 where X isphenyl optionally substituted with one or more substituents selectedfrom F, Cl, CN, NO₂, CF₃, OCF₃, OCHF₂, CH₂CF₃ and OMe.
 60. The compoundof claim 1 where X is selected from a 3,4-disubstituted phenyl,3-substituted phenyl and 4-substituted phenyl.
 61. The compound of claim1 where X is selected from 3,4-disubstituted phenyl and 4-substitutedphenyl.
 62. The compound of claim 1 where X is 4-substituted phenyl. 63.The compound of claim 1 where X is selected from benzo[d]oxazoyl,benzo[c][1,2,5]oxadiazyl, benzo[c][1,2,5]thiadiazolyl,benzo[d]isoxazolyl, 1H-benzo[d]imidazoyl, benzo[d]thiazoyl,benzo[c]isothiazolyl, benzo[d]isothiazolyl, benzo[c]isoxazolyl,imidazo[1,2-a]pyridinyl and imidazo[1,5-a]pyridinyl. 64-112. (canceled)113. A method for treating a CNS disorder comprising administering to ahuman thereof a therapeutically effective amount of the compound ofclaim
 1. 114. A method for treating eating disorders, obesity,compulsive gambling, sexual disorders, narcolepsy, sleep disorders orfor use in smoking cessation treatment comprising administering to ahuman thereof a therapeutically effective amount of the compound ofclaim
 1. 115. A method for treating obesity, schizophrenia,schizo-affective conditions, Huntington's disease, dystonic conditionsand tardive dyskinesia comprising administering to a human thereof atherapeutically effective amount of the compound of claim
 1. 116-118.(canceled)